Therapeutic ultrasound for eye disorders

ABSTRACT

Methods and devices are described which allow sound waves to be safely be applied to the eyelid of an eye of a patient or through the eyelid to other structures in the eye or to or through structures in the facial region to effect changes to one or more structures in and around the eye or directly through the cornea or sclera to regions of the eye to treat one or more diseases of the eye.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/250,571 (Attorney Docket No. 52608-703.301), filed Jan. 17, 2019,which is a continuation of U.S. patent application Ser. No. 15/783,872(Attorney Docket No. 52608-703.201), filed Oct. 13, 2017, which claimsthe benefit of U.S. Provisional Application No. 62/521,362 (AttorneyDocket No. 52608-703.106), filed Jun. 16, 2017; U.S. ProvisionalApplication No. 62/509,238 (Attorney Docket No. 52608-703.105), filedMay 24, 2017; U.S. Provisional Application No. 62/451,583 (AttorneyDocket No. 52608-703.104), filed Jan. 27, 2017; U.S. ProvisionalApplication No. 62/422,627 (Attorney Docket No. 52608-703.103), filedNov. 16, 2016; and U.S. Provisional Application No. 62/410,115 (AttorneyDocket No. 52608-703.102), filed Oct. 19, 2016; and U.S. ProvisionalApplication No. 62/408,651 (Attorney Docket No. 52608-703.101), filedOct. 14, 2016, each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates generally medical devices and methods.More particularly, the present invention relates to devices and methodsfor treating an eye.

Therapeutic sound and ultrasound have become an increasingly commonmodality in treating medical disorders. The ability to deliver bothsound and ultrasound non-invasively is of increasing interest in themedical community. In ophthalmology, therapeutic sound and ultrasoundare of particular interest because of its non-invasive nature andability to easily reach all structures inside the eye and becauseultrasound imaging can easily image all the structures in the eye.

The inventions contained herein all utilize therapeutic sound orultrasound in the treatment of disorders involving the head and neck.Sound and ultrasound are also contained in the broad category ofmechanical vibration.

2. Description of the Background Art

A device to create tearing to treat dry eye has recently been developed(U.S. Pat. No. 9,440,065) which utilizes an intranasal neurostimulatorto activate nerves in the nasal mucosa. This device is placed inside thenostrils and two prongs grab onto the septum after which electricalcurrent is applied across the septum. According to the company andresearch in the field, the electrical stimulation activates the interiorbranch of the anterior ethmoidal nerve. Within a few minutes, tears aregenerated. A randomized showed that the device, when placedintranasally, compared to sham, was highly effective in producing tears(product brochure; www.truetear.com), tears which contain the typicalconcentration of proteins and glycoproteins. The sham procedure was onein which the same neurostimulation device and parameters were applied tothe skin on the outer nostril. The sham procedure on the outer skin ofthe nostril did not change the baseline amount of tearing from baselineand served as an outstanding control. The intranasal neurostimulator wasuncomfortable for many patients and resulted in a great number of sideeffects including an epistaxis rate of over 5 percent. Most patientsalso reported that they would not perform the procedure in publicalthough their symptoms were dramatically improved.

Another dry eye treatment involves a procedure in which a lens is placedover the cornea and a device then compresses the eyelid between thedevice and the cornea, applying both pressure and heat (e.g. U.S. Pat.No. 7,976,573, www.tearscience.com). The procedure is performed in anophthalmologist office and the device has been shown to open the glandson the inside of the eye, called Meibomian Glands (and the disease iscalled Meibomian Gland Disease or MGD). This device also had been shownto be effective for dry eye in clinical trials but is also cumbersomeand expensive for an ophthalmologist and patients, lasting about 30 minto an hour inside a physician's office.

See also US2016/0158548; US2015/0100001; US2011/0319794; andUS2011/0190668.

While these devices represent advances in the treatment of dry-eye, newmethods and devices are needed to treat dry eye and associated lack ofability to produce tears and maintain sufficient Meibomian glandsecretions. The devices should also be designed with a low cost and formfactor which encourages compliance and facilitates their utilization. Atleast some of these advantages will be met by the inventions describedherein below.

SUMMARY OF THE INVENTION

In an exemplary first aspect, the present invention provides a methodfor stimulating tear production in a patient. The method comprisespositioning a vibratory surface at a bony region on the patient's facecommunicating with a parasympathetic nerve which innervates the lacrimalgland. The vibratory surface is vibrated at a frequency and adisplacement selected to stimulate the lacrimal nerve to produce tears.Typically, the vibratory surface will stimulate an afferent whichcommunicates with a parasympathetic nerve which stimulates glandsrelated to the tear film.

The vibratory surface may be vibrated at any frequency effective tostimulate the target nerves, typically being in a range from 10 Hz to1000 Hz, 10 Hz to 500 Hz, 10 Hz to 400 Hz, 10 Hz to 300 Hz, 10 Hz to 200Hz, 10 Hz to 100 Hz, 10 Hz to 50 Hz, 50 Hz to 1000 Hz, 50 Hz to 500 Hz,50 Hz to 400 Hz, 50 Hz to 300 Hz, 50 Hz to 200 Hz, 50 Hz to 100 Hz, 200Hz to 1000 Hz, 200 Hz to 500 Hz, 200 Hz to 400 Hz, 200 Hz to 300 Hz, 300Hz to 1000 Hz, 300 Hz to 500 Hz, 300 Hz to 400 Hz, or 400 Hz to 1000.Similarly, the vibratory surface may be vibrated at any displacementeffective to stimulate the target nerves, typically being in a rangefrom 0.1 mm to 5 mm, 0.25 mm to 5 mm, 0.5 mm to 5 mm, 1 mm to 5 mm, 0.1mm to 3 mm, 0.25 mm to 3 mm, 0.5 mm to 3 mm, 1 mm to 3 mm, 0.1 mm to 5mm, 0.25 mm to 2 mm, 0.5 mm to 2 mm, 1 mm to 2 mm, or 2 mm to 3 mm.

The vibratory surface typically has a skin contact area in a range from0.5 mm² to 20 mm², 0.5 mm² to 10 mm², 0.5 mm² to 5 mm², 0.5 mm² to 2mm², 0.5 mm² to 1.5 mm², 0.5 mm² to 1 mm², 1 mm² to 20 mm², 1 mm² to 10mm², 1 mm² to 5 mm², 1 mm² to 2 mm², 1 mm² to 1.5 mm², 1.5 mm² to 20mm², 0.5 mm² to 10 mm², 1.5 mm² to 5 mm², 1.5 mm² to 2 mm², 2 mm² to 20mm², 2 mm² to 10 mm², 2 mm² to 5 mm², 2.5 mm² to 20 mm², 2.5 mm² to 10mm², 2.5 mm² to 5 mm², 5 mm² to 20 mm², or 5 mm² to 10 mm².

The vibratory surface typically has a hardness in a range from Shore A40to Shore A80, Shore A50 to Shore A80, Shore A60 to Shore A80, Shore A70to Shore A80, Shore A40 to Shore A70, Shore A50 to Shore A70, Shore A60to Shore A70, Shore A40 to Shore A60, Shore A50 to Shore A60, or ShoreA40 to Shore A50.

The vibratory surface is usually formed on a polymeric interface bodyand may have a thickness in a range from 1 mm to 10 mm, 2 mm to 10 mm, 3mm to 10 mm, 4 mm to 01 mm, 5 mm to 10 mm, 6 mm to 10 mm, 7 mm to 10 mm,8 mm to 10 mm, 9 mm to 10 mm, 1 mm to 5 mm, 2 mm to 5 mm, 3 mm to 5 mm,4 mm to 5 mm, 1 mm to 4 mm, 2 mm to 4 mm, 3 mm to 4 mm, 1 mm to 3 mm, 2mm to 3 mm, or 1 mm to 2 mm.

The polymeric interface body may have a rounded edge circumscribing atleast a portion of the vibratory surface. Such a rounded edge may have aradius in a range from 0.5 mm to 5 mm, 1 mm to 5 mm, 2 mm to 5 mm, 3 mmto 5 mm, 4 mm to 5 mm, 0.5 mm to 4 mm, 1 mm to 4 mm, 2 mm to 4 mm, 3 mmto 4 mm, 0.5 mm to 3 mm, 1 mm to 3 mm, 2 mm to 3 mm, 0.5 mm to 2 mm, 1mm to 2 mm, and 0.5 mm to 1 mm. Alternatively, the polymeric interfacebody may have a square edge circumscribing at least a portion of thevibratory surface. The edge may or may not have the same properties as acentral portion of the vibratory surface. For example, the polymericinterface body may have a rigid edge circumscribing at least a portionof the vibratory surface. The method of any one of claim 1, wherein thevibratory surface is vibrated with a pulsed duty cycle or 90%, 75%, 50%,25% or 10%.

In some embodiments, a peak displacement of the vibratory surface may beincreased when the duty cycle is less than 100%.

In some embodiments, the vibratory surface may be positioned on thepatient's face at a location where the patient's upper lateral nasalcartilage meets the patient's nasal bone. In such cases, the vibratorysurface may be engaged against the patient's face with an upwarddirectionality.

In some embodiments, the vibratory surface may be positioned at alocation from 6.5 mm to 8.5 mm lateral to the patient's nasal midline atthe region.

In some embodiments, the vibratory surface may be positioned proximateor over the parasympathetic nerve which innervates the lacrimal glandand travels through the sphenopalatine ganglia located close to themaxillary bone in the sphenopalatine fossa.

In some embodiments, the vibratory surface may be positioned by engagingthe vibratory surface on a hand held device against the bony region.Usually, a patient engages the vibratory surface of the hand held deviceagainst the bony region.

In some embodiments, the vibratory surface moves in a substantiallylinear direction in one dimension. For example, the vibratory surfacemay be driven in a substantially linear direction with an excursion of0.5 to 2 mm.

In some embodiments, the vibratory surface may be placed in a positionto stimulate the external nasal nerve.

In an exemplary second aspect, the present invention provides a handhelddevice for stimulating tear production in a patient. The devicecomprises a housing having a vibratory surface configured to engage abony region on the patient's face over an afferent nerve whichcommunicates with a parasympathetic nerve which innervates glandsrelated to the tear film. Circuitry within the housing is configured tovibrate the vibratory surface at a frequency and a displacement selectedto stimulate the afferent nerve, the lacrimal nerve to produce tears,and the Meibomian glands to produce oils to maintain the tear film.

Exemplary frequencies, displacements, skin contact areas for thevibratory surfaces, and other design features of the vibratory surfacesand devices have been set forth above with respect to the firstexemplary aspects of the present invention.

In other aspects of the methods and hand held device of the presentinvention, the device circuitry may be configured to vibrate vibratorysurface with a pulsed duty cycle or 90%, 75%, 50%, 25% or 10%. Inspecific embodiments, the circuitry may be configured to increase a peakdisplacement of the vibratory surface when the duty cycle is less than100%.

The hand held device may be configured to be positioned by the patientso that the vibratory surface engages the vibratory surface against thebony region.

The circuitry may be configured to allow adjustment of the vibrationalfrequency. For example, the hand held device may include a manualfrequency adjustment interface.

In an exemplary third aspect, the present invention provides a methodfor stimulating tear production in a patient. The method comprising (a)retracting an eyelid and (b) engaging a vibratory surface against theretracted eyelid at a frequency and a displacement selected to stimulatetear production, Meibomian gland secretion, or both.

In this method, the retracted eyelid may be compressed between aretractor and a compression member, and a vibratory surface may beengaged against the retracted eyelid by energizing at least onetransducer on at least one of the retractor and the compression member.

The at least one transducer will typically be an ultrasound transduceroperating at a frequency in a range from 20 kHz to 30 MHz or from 3 MHzand 10 MHz, and the ultrasound vibration typically penetrates the eyelidand heats a tissue plane inside the lid such that a surface of theeyelid remains substantially at body temperature (38° C. to 40° C.)while the inner eyelid is heated to from (42° C. to 48° C.).

In an exemplary fourth aspect, the present invention provides a handheld device for stimulating tear production in a patient. The devicecomprises a retractor having an eyelid-engaging end and a handle end. Avibrational transducer is located on the eyelid-engaging end of theretractor and is configured to deliver vibrational energy into theeyelid when the eyelid is engaged by the eyelid-engaging end of theretractor.

The vibrational transducer of the hand held device is typically at leastone ultrasonic vibrational transducer, usually operating at a frequencyin a range from 20 kHz to 30 MHz or from 3 MHz and 10 MHz. The hand helddevice may further comprise at least one non-ultrasonic vibrationaltransducer, typically operating at a frequency in a range from 10 Hz to1000 Hz, 10 Hz to 500 Hz, 10 Hz to 400 Hz, 10 Hz to 300 Hz, 10 Hz to 200Hz, 10 Hz to 100 Hz, 10 Hz to 50 Hz, 50 Hz to 1000 Hz, 50 Hz to 500 Hz,50 Hz to 400 Hz, 50 Hz to 300 Hz, 50 Hz to 200 Hz, 50 Hz to 100 Hz, 200Hz to 1000 Hz, 200 Hz to 500 Hz, 200 Hz to 400 Hz, 200 Hz to 300 Hz, 300Hz to 1000 Hz, 300 Hz to 500 Hz, 300 Hz to 400 Hz, or 400 Hz to 1000 Hz.

In an exemplary fifth aspect, the present invention provides method forstimulating tear production in a patient. The method comprising (a)retracting an eyelid and (b) engaging a vibratory surface against theretracted eyelid at a frequency and a displacement selected to openMeibomian glands in the patient.

These methods may further comprising any one or more of measuring thetemperature of the inner and/or outer eyelid, compressing the eyelidwhile the vibratory surface is applied, placing the vibratory surfaceagainst the inner portion of the eyelid, placing the vibratory surfaceagainst the outer part of the eyelid.

In an exemplary sixth aspect, the present invention provides hand helddevice for stimulating tear production in a patient. The devicecomprises a retractor having an eyelid-engaging end and a handle end. Apushrod having a distal member is configured to slide on the handle endto capture a patient's eyelid between the retractor and the distalmember. A vibrational transducer on the eyelid-engaging end of theretractor is configured to deliver vibrational energy into the eyelidwhen the eyelid captured between the retractor and the distal member.

In particular examples of the hand held device, the pushrod may bespring-biased to open and manually advanced to close over the eyelid.The hand held device may further comprise a force gauge to indicate aforce being applied to the eyelid. The vibrational transducer maygenerate ultrasound at frequencies from 20 KHz to 30 MHz to heat theeyelid to disrupt inspissation in blocked ducts. Alternatively, thevibrational transducer may generates ultrasound at frequencies from 500kHz and 3 MHz to heat the eyelid to disrupt inspissation in blockedducts. The hand held device may further comprise a control system tomaintain a temperature between 40° C. and 47° C.

In one embodiment, an ultrasound adjunct for placement inside an eyelidto augment the ability to apply heat to the inside of the eyelid whileprotecting the surface of the eye is described.

In one embodiment, therapeutic ultrasound is projected to the posteriorvitreous to repair or prevent a macular hole by completing a posteriorvitreal detachment.

In some embodiments, therapeutic ultrasound is utilized to improve(speed and quantity) of drug delivery to structures including theretina, eyelid and associated glands and structures, the optic nerve,the lens, the trabecular meshwork, the cornea, and the anterior chamberof the eye.

In some embodiments, therapeutic ultrasound is utilized to open waterpores in the retina to deliver drugs, genes, or materials to the retinaand/or choroid.

In some embodiments, therapeutic ultrasound is utilized to mix drugs inthe posterior vitreous cavity.

In some embodiments, therapeutic ultrasound is utilized to propelbioactive agents to the posterior of the eye.

In some embodiments, therapeutic ultrasound is utilized to repairinjured retinal cells with low intensity stimulation of the retina.

In some embodiments, therapeutic ultrasound is used to break up floatingdebris in the vitreous.

In some embodiments, therapeutic ultrasound is used to liquefy theposterior vitreous to treat floaters.

In some embodiments, therapeutic ultrasound is utilized to createlocalized regions of drug uptake within the retina or the optic nerve.

In some embodiments, therapeutic ultrasound is utilized to assist inemulsifying the lens.

In some embodiments, therapeutic ultrasound is utilized to open uptrabeculae and allow drainage of aqueous humor to decrease intra-ocularpressure.

In some embodiments, therapeutic ultrasound is utilized to inhibit fluidproduction from the ciliary processes in the eye.

In some embodiments, the therapeutic ultrasound is focused.

In some embodiments, the therapeutic ultrasound is unfocused or softlyfocused on the posterior vitreous cavity or other ocular structure beingtreated.

In some embodiments, therapeutic ultrasound is coupled to an imagingmodality such as Optical Coherence Tomography, Ultrasound imaging, CT,MRI, optical imaging, and fluorescein angiography.

In some embodiments, therapeutic ultrasound is coupled to a laser beam.

In some embodiments, therapeutic ultrasound is coupled to ophthalmicimaging.

In some embodiments, therapeutic ultrasound is coupled to opticalcoherence tomography.

In some embodiments, therapeutic ultrasound is utilized to break upblood clots within blood vessels in the eye.

In some embodiments, therapeutic ultrasound is coupled to administrationof systemic pharmaceutical agents.

In some embodiments, therapeutic ultrasound to the retina is coupled totreatment with systemically administered lytic agents to enhance breakupof clots in the retina.

In some embodiments, therapeutic ultrasound is utilized in combinationwith ultrasound sensitizing agents to enhance the effect.

In some embodiments, therapeutic ultrasound is utilized in combinationwith microbubbles.

In some embodiments, therapeutic ultrasound is utilized in combinationwith genetically engineered viruses or proteins, the therapeuticultrasound stimulating or enhancing uptake of the viruses or proteins.

In some embodiments, therapeutic ultrasound is utilized in combinationwith ultrasound sensitive proteins, nanoparticles, or other bioactivematerials.

In some embodiments, high intensity focused therapeutic ultrasound isutilized to create histotripsy damage in structures of the eye.

In some embodiments, a frequency below 1 megahertz is utilized.

In some embodiments, a frequency greater than 1 megahertz is utilized.

In some embodiments, low intensity is utilized to create a therapeuticeffect.

In some embodiments, frequency between 50 and 300 Hz is utilized.

In some embodiments, high intensity ultrasound is utilized to create atherapeutic effect.

In some embodiments, ionizing radiation is used in combination withtherapeutic ultrasound.

In some embodiments, therapeutic ultrasound is utilized to break upfibrotic tissues in the retina and allow for improved drug access.

In some embodiments, therapeutic sound or ultrasound or mechanicalvibrations is utilized to treat dry eye by stimulating the lacrimalglands or the nasolacrimal duct.

In some embodiments, therapeutic ultrasound is utilized to stimulatenerves which travel to the lacrimal gland in the eye.

In some embodiments, therapeutic ultrasound is utilized to open upMeibomian glands inside an eyelid.

In some embodiments, therapeutic ultrasound or sound is utilized tostimulate a lacrimal duct via the nose in a patient.

In some embodiments, therapeutic sound or ultrasound is utilized tostimulate secretion of tears.

In some embodiments, therapeutic sound or ultrasound or mechanicalvibration is utilized to stimulate the external branch of the anteriorethmoidal nerve (external nasal nerve) to create tears or decongest thesinus or nasal cavities.

In some embodiments, therapeutic ultrasound sound or mechanicalvibration is utilized to decrease outflow from ciliary processes totreat elevated intraocular pressure.

In some embodiments, therapeutic ultrasound is utilized to increase thepore size within the trabecular meshwork of the eye to allow increasedoutflow and decrease intraocular pressure.

In some embodiments, therapeutic ultrasound is utilized to enhance drugdelivery to the aqueous humor in the front the eye.

In some embodiments, therapeutic ultrasound is utilized to enhance drugdelivery to treat glaucoma.

In some embodiments, therapeutic sound or ultrasound or vibration isutilized to treat red-eye.

In some embodiments, therapeutic ultrasound is utilized to treatinfected tissues in the eye.

In some embodiments, therapeutic sound, ultrasound, or mechanicalvibration is utilized to treat macular degeneration.

In some embodiments, therapeutic sound, vibration, or ultrasound isutilized to treat or prevent dry macular degeneration.

In some embodiments, therapeutic ultrasound is utilized to treat orprevent the formation of pterygium.

In some embodiments, therapeutic sound, vibration, or ultrasound isutilized to enhance drug delivery to the eyelid.

In some embodiments, therapeutic ultrasound utilized to enhance drugdelivery to the eyelashes to improve their appearance or enhance theirgrowth.

In some embodiments, therapeutic ultrasound, vibration, or sound isutilized to enhance eyelash growth with or without the addition ofpharmaceutical agents.

In some embodiments, therapeutic ultrasound is utilized to enhance druguptake to improve healing after a surgical procedure to the cornea.

In some embodiments, therapeutic ultrasound is utilized to remove ortighten loose or wrinkled skin of the eye of around the eyelid.

In some embodiments, therapeutic ultrasound is utilized to aid inhealing of the retina with or without drug delivery after a surgicalprocedure.

In some embodiments, therapeutic ultrasound is utilized to apply forceto retina to push fluids into the retina or through Bruch's membrane,the choroid, or the choriocapillaris layer of the retina.

In any of the embodiments of this invention, therapeutic ultrasound isreplaced with therapeutic sound such as with frequency below 1000 Hz orstraight mechanical vibration without sound.

In any of the embodiments above, therapeutic ultrasound is replaced withtherapeutic sound such as sound with a frequency below 500 Hz.

In some embodiments, therapeutic sound is coupled to skin covering bonystructures and a frequency of sound is applied to the skin such that thebone underneath resonates in response to the sound and the resonationthrough the bone activates nerves in close proximity to the bone.

In some embodiments, therapeutic sound is delivered through endeffectors which propagate the sound and transduce it to the bonystructures of the head and neck with optimal safety and effectiveness.

In some embodiments, therapeutic sound is used to stimulate thesphenopalatine ganglia and associated nerves in the pterygopalatinefossa by transducing sound through the skin overlying the maxillarybone.

In some embodiments, therapeutic sound or ultrasound is used tostimulate the sphenopalatine ganglia and interfere with migraines,cluster headaches, or seizures.

In some embodiments, therapeutic sound, vibration, or ultrasound is usedto stimulate saliva production.

In some embodiments, therapeutic sound, vibration, or ultrasound isutilized to stimulate the external branch of the anterior ethmoidalnerve (external nasal nerve) at the region of the nose where the nasalbone meets the lateral process of the septal nasal cartilage.

In some embodiments, therapeutic sound or ultrasound is utilized tostimulate the sphenopalatine ganglia to treat cold symptoms such asstuffed or congested nasal passageways.

In some embodiments, therapeutic sound, vibration, or ultrasound isutilized to inhibit the sphenopalatine ganglia.

In some embodiments, therapeutic sound, vibration, or ultrasound isutilized to treat or eliminate wrinkles or loose skin of the eyelids ofan eye.

In some embodiments, external ultrasound and/or mechanical vibration areapplied to a nerve of the facial region to treat headache, rhinitis,depression, Alzheimer's disease, stroke, Parkinson disease, Meniere'sdisease, tinnitus.

In some embodiments, external ultrasound and/or mechanical vibration areapplied to the region where the nasal bone meets the nasal cartilage tostimulate the nerves related to the sphenopalatine ganglia or theethmoidal nerves to increase tears and to treat dry eye.

The following numbered clauses represent other specific aspects of thepresent invention:

1. A method to treat a nerve of the facial region comprising:

a. Applying a handheld device with an applicator tip to the skin of aface of a patient, the skin covering a facial bony region immediatelythereunder;

b. Depressing the applicatory tip on the skin toward the bone of theface of the patient such that further depression is prevented;

c. Delivering vibratory energy from the handheld device, through theapplicator tip of the device, through the skin of the patient andthrough the bone of the patient to stimulate or inhibit a nerve of thehead and neck region of the patient.

2. The method of clause 1 wherein the vibratory energy has a frequencyfrom about 50 Hz to about 1 KHz.

3. The method of clause 1 wherein the vibratory energy has a frequencyfrom about 100 Hz to about 500 Hz.

4. The method of clause 1 wherein the handheld device is applied to theside of a nose of patient and depressed against the nasal bone along theside of the nose at the region where the cartilage meets the bone tostimulate tears in the patient.

5. The method of clause 1 wherein the handheld device is applied to theside of a nose of the patient at the location where the nasal cartilageand the nasal bone meet.

6. The method of clause 1 wherein the handheld device is depressed alongthe side of the nose at the location where the nasal cartilage and thenasal bone meet; and, applying a finger to the contralateral side of thenose concomitantly.

7. The method of clause 1 wherein the handheld device is applied to bothsides of the nose of the patient either simultaneously or sequentiallyduring therapy.

8. The method of clause 1 wherein the handheld device delivers vibratoryenergy at a decibel level less than about 20 db.

9. The method of clause 1 where the handheld device delivers thevibratory energy at a decibel level less than about 10 db.

10. The method of clause 1 further comprising: stimulating a nerve ofthe head and neck region to create tearing from the eye.

11. The method of clause 1 further comprising: stimulating asphenopalatine ganglia of the patient to generate tears from thelacrimal gland of the patient.

12. The method of clause 1 further comprising: stimulating thenasolacrimal duct to generate tears in the eye of the patient.

13. The method of clause 1 wherein the vibratory frequency is adjustedto optimize the stimulation or inhibition of the nerve.

14. The method of clause 1 wherein the vibratory amplitude is adjustedto optimize the stimulation or inhibition of the nerve.

15. The method of clause 1 further comprising: attaching the applicatortip to a finger tip and pressing the finger tip to the skin of the nosein the region where the nasal bone meets the nasal cartilage.

16. The method of clause 1 further comprising attaching the applicatortip to two fingers; and, applying the vibratory energy to the bone bypinching the region of the nose with the two fingers.

17. The method of clause 1 further comprising: holding the applicator toone side of the nose with a first hand while adjusting its pressure onthe skin by pressing against the other side of the nose with a differentfinger of the same hand.

18. The method of clause 1 further comprising one of: adjusting theangle of application, the pressure against the skin, and the type ofapplicator tip based on feedback from the patient of a sensation oftearing.

19. The method of clause 1 further comprising touching the applicatortip to a region of the face to affect a change in a congestion conditionsuch as one of: sinusitis, nasal congestion, and rhinitis.

20. A device to stimulate a nerve in the head and neck region of apatient comprising:

a. an applicator with a connected applicator handle, an actuator coupledto the handheld applicator, and a body surface interface mechanicallycoupled to the actuator;

b. wherein the actuator moves mechanically at a frequency driven by anelectric current and voltage to generate vibrational energy;

c. and, wherein the body surface interface is adapted to couple to askin interface of the head and neck region of the patient to transmitvibrational energy to a bone through the skin, and to stimulate a nerveacoustically coupled to the bone through the skin.

21. The device of clause 20 wherein the actuator vibrates at a frequencyof between 100 and 300 Hz.

22. The device of clause 20 wherein the actuator is coupled to amaterial such that the material moves with a planar excursion of about500 microns and not more than about 1500 microns.

23. The device of clause 20 wherein the body surface interface isadapted to couple to a nasal bridge.

24. The device of clause 20 wherein the body surface interface isadapted to simultaneously couple to both sides of a nose.

25. The device of clause 20 wherein the body surface interface has thecompliance of a pencil eraser.

26. The device of clause 20 wherein the handheld applicator is adaptedto be worn on a wrist and the actuator is separated from the handheldactuator by a flexible wire.

27. The device of clause 26 wherein the handheld applicator furthercomprises a portable battery.

28. The device of clause 20 wherein the nerve is part of, orcommunicates with, a sphenopalatine ganglia.

29. The device of clause 20 wherein the vibrational energy is configuredto resonate with the bone overlying the nerve to stimulate the nerve.

30. The device of clause 20 wherein the skin surface interface isadapted to be grasped between the fingers of the patient.

31. The device of clause 20 wherein the skin surface interface isconnected to a pair of spectacles.

32. The device of clause 20 wherein the skin surface interface furthercomprises a combination of a rigid material and a malleable material.

33. The device of clause 32 wherein the skin surface interface furtheris adapted to direct the vibrational energy preferentially in onedirection to couple the vibrational energy to the bone underlying theskin and the handheld applicator is isolated from the movement andvibration.

34. The device of clause 20 wherein the nerve is a branch of facialnerve.

35. The device of clause 20 wherein the nerve is a lacrimal nerve.

36. The device of clause 20 wherein the nerve is a nerve whichinnervates a parotid or salivary gland.

37. The device of clause 20 further comprising an adjustment control tovary the vibration frequency and/or the amplitude of the actuator.

38. The device of clause 20 wherein the applicator is handheld.

39. The device of clause 20 wherein the applicator is configured to beattached to a finger.

40. The device of clause 20 wherein the applicator is configured to beattached to two fingers such that the bridge of the nose can be pinchedwith two actuators to transmit vibration to the nerve of the head orneck region simultaneously.

41. The device of clause 20 wherein the applicator is configured to beattached to the wrist of the patient.

42. The device of clause 20 wherein the applicator is configured to beattached to a pair of spectacles.

43. The device of clause 20 wherein the applicator is configured to beapplied to an eyelid appliance.

44. The device of clause 20 wherein the body surface interface isadapted to couple vibrations from the actuator to the bone underneaththe skin.

45. The device of clause 20 wherein the body surface interface comprisesa semi-rigid material.

46. The device of clause 20 wherein the body surface interface isadapted to couple to the finger of a user and wherein the body surfaceinterface further comprises a second interface which couples to a secondfinger of a user.

47. The device of clause 20 wherein the body surface interface comprisesa shape memory material to facilitate form fitting to the tissue of theouter region of a nose of a user.

48. The device of clause 20 further comprising a controller whichenables modulation of the amplitude of the vibration of the body surfaceinterface.

49. The device of clause 20 wherein the vibrational energy is adapted toactivate a pressure sensitive nerve.

50. The device of clause 20 wherein the actuator imparts motion to thebody surface interface in which the motion is linear and is adapted toapply to the skin surface so that the motion is approximatelyperpendicular to the skin surface.

51. The device of clause 20 wherein the actuator imparts motion to thebody surface interface in which the motion is linear and is adapted toapply to the skin surface so that the motion is perpendicular to theskin surface and can be adjusted so that the motion is applicable at anangle to the skin surface.

52. The device of clause 20 wherein the actuator imparts motion to thebody surface interface in which the motion is linear and is adapted toapply to the skin surface while vibrations to the hand of the user areminimized.

54. The device of clause 20 wherein the actuator is electricallyconnected to a controller in which the controller imparts an adjustablefrequency control.

55. The device of clause 20 wherein the actuator is electricallyconnected to a controller in which the controller imparts an adjustableamplitude control.

57. The device of clause 20 wherein the actuator is a solenoid with anelectromagnet to impart linear direction to the body surface interface.

59. The device of clause 20 wherein the actuator is a speaker or a voiceactivated coil.

60. The device of clause 20 wherein the actuator has a linear actuatorcomponent vibrations are isolated from the user of the device.

61. The device of clause 20 wherein the body surface interface is rigidwith an edge of approximately 1-2 mm width and configured to fit in theridge at the junction of the nasal bone and nasal cartilage.

62. The device of clause 20 wherein the body surface interface furthercomprises an edge adapted to at least partially retract an eyelid.

63. The device of clause 20 wherein the actuator is connected to cam andwherein the cam drives a piston to create a linear motion.

64. The device of clause 63 wherein the cam is attached to a rod whichconnects to a position offset from the central axis of the motor so asto create a linear motion of the piston, the excursion of which isproportional to the offset from the central axis.

65. The device of clause 64 wherein the offset results in a 1 mmexcursion of the piston.

66. The device of clause 64 wherein the offset results in a 2 mmexcursion of the piston.

67. The device of clause 64 wherein the offset results in a 0.5 mmexcursion of the piston.

68. The device of clause 64 further comprising an electronic controlcircuit wherein the electronic control circuit outputs a programmablevoltage which determines the revolutions per minute of the motor andtherefore the excursion frequency of the piston.

69. The device of clause 63 wherein the linear motion applicator isadapted to apply a force of about 1 N to 5 N to a region of the faceoverlying a nerve to activate the nerve with periodic application ofthis force through the skin to reach the nerve underlying the skin tocreate a clinical effect in a patient.

70. A method to treat a patient with a headache comprising:

a. applying a handheld device to the skin overlying a nerve on the facewhich communicates with an autonomic nervous center, the handheld deviceconfigured to generate pressure waves;

b. activating the handheld device at the time of a headache to transmitthe pressure waves through the skin and through the bone to activate theautonomic nervous system.

71. The method of clause 70 further comprising applying sound wavesacross the skin to activate the autonomic nervous system.

72. The method of clause 70 further comprising: placing the handhelddevice on the region along the skin along the side of the nose where thenasal bone and the nasal cartilage meet; firmly pressing into thisregion; and, applying vibratory energy from the handheld device with afrequency of about 100-300 Hz and an excursion of the device tip ofabout 0.5 mm to about 1.5 mm.

73. The method of clause 70 further comprising targeting the anteriorethmoidal nerve.

74. The method of clause 70 further comprising: setting the handhelddevice to generate ultrasound pressure waves with frequency of about 500kHz to about 5 MHz.

75. The method of clause 70 further comprising activation the anteriorethmoidal nerve.

76. The method of clause 70 further comprising applying pressure to thehandheld device along the skin of the patient so that the patient feelsa sneezing or tearing sensation.

77. The method of clause 70 further comprising applying a range offrequencies of pressure waves to determine the optimal frequency anddegree of pressure to achieve the effect of preventing the headache.

78. The method of 70 wherein a sphenopalatine ganglia is activated byapplying the handheld device to the external nasal nerve.

79. A method to treat a nerve of the facial region comprising:

a. applying a handheld device with an applicator tip to the skin of aface of a patient, the skin covering a bony region of the face;

b. depressing the application tip on the skin toward the bone of theface of the patient;

c. delivering vibratory energy from the handheld device, through theapplicator tip of the device, through the skin of the patient andthrough the bone of the patient to create a biologic effect in a mucosalregion underlying the bone.

80. The method of clause 79 further comprising: delivering the vibratoryenergy via applicator tip with a frequency of approximately 100-300 Hzand an excursion of 0.5 m to 2.0 mm.

81. The method of clause 79 further comprising: delivering vibratoryenergy via applicator tip with a frequency of approximately 300 Hz to 50kHz.

82. The method of clause 79 further comprising: delivering vibratoryenergy via applicator tip with a frequency of approximately 50 kHz to 10MHz.

83. The method of clause 79 further comprising: delivery a bioactiveagent before, during, or after the vibratory energy.

84. The method of clause 79 further comprising applying the vibratoryenergy to an implant.

85. The method of clause 79 further comprising applying the vibratoryenergy before, during, or after a surgical procedure.

86. The method of clause 79 further comprising applying at least twodifferent modes of vibratory energy simultaneously to effect a change inthe mucosa of the sinus.

87. A method to treat a nerve of the facial region comprising:

a. applying a handheld device with an applicator tip to the skin of aface of a patient, the skin covering a bony region of the face, the bonyregion coupled to an autonomic nerve;

b. depressing the application tip on the skin toward the bone of theface of the patient;

c. delivering vibratory energy from the handheld device, through theapplicator tip of the device, through the skin of the patient andthrough the bone of the patient to create a biologic effect in a mucosalregion underlying the bone.

88. The method of clause 87 wherein the mucosal region is a sinus cavityor a nasal passage.

89. The method of clause 87 wherein the vibratory energy has a frequencyof between 50 Hz and 5 MHz.

90. The method of clause 87 wherein a bioactive agent is applied to themucosa prior to application of the vibratory energy.

91. The method of clause 87 wherein the biologic effect is disruption ofthe biofilm layer in the mucosal region.

92. The method of clause 87 wherein the mucosal region contains a nerve.

93. The method of clause 87 further comprising: cycling the vibratorypower with a duty cycle, a peak power, and an average power.

94. The method of clause 87 further comprising performing a surgicalprocedure prior to, during or after delivery of the vibrational energy.

95. The method of clause 87 further comprising locating a sinus or aregion of congestion using an acoustic impulse.

96. The method of clause 87 further comprising: simultaneously utilizingmultiple vibratory frequencies.

97. The method of clause 87 further comprising: applying one vibratoryenergy with a frequency between 50 and 300 Hz and a second vibratoryenergy of between about 1 MHz and 30 MHz.

98. The method of clause 87 further comprising: mapping the nerveanatomy of the nasal region prior to applying the vibratory energy.

99. The method of clause 87 further comprising: activating the activatortip to deliver vibratory energy with a frequency between 1 MHz and 10MHz.

100. The method of clause 87 further comprising: activating theactivator tip to deliver vibratory energy with a frequency between 0.5MHz and 5 MHz.

101. The method of clause 87 further comprising: activating theactivator tip to deliver a vibratory energy with a frequency between 50Hz and 500 Hz.

102. The method of clause 87 further comprising: stimulating aparasympathetic nerve to create a tearing response.

103. The method of clause 87 further comprising: activating an implantto release a bioactive molecule into the mucosa.

104. The method of clause 87 further comprising: activating a polymer torelease a bioactive molecule into the mucosa.

105. A method to treat patient with dry eye comprising:

a. applying a handheld device with an applicator tip to the skin of aface of a patient, the skin covering a bony region of the face;

b. depressing the applicator tip on the skin toward the bone of the faceof the patient in the region where the nasal cartilage meets the nasalbone;

c. delivering vibratory energy from the handheld device with a frequencybetween 100 Hz and 400 Hz and an amplitude of the applicator tip greaterthan 500 microns to the region where the nasal cartilage meets the nasalbone to stimulate tears in the eyes of the patient.

106. The method of clause 105 further comprising: setting the frequencyto a frequency between 150 and 200 Hz.

107. The method of clause 105 further comprising adding a bioactiveagent to the wherein the feedback from the stimulation of the nerve isutilized to ensure the intended nerve has been treated

108. A method to treat a patient with nasal or sinus disease comprising:

a. applying a sound or ultrasound applicator to the skin surrounding thenasal sinuses;

b. setting an amplitude and a frequency of the applicator applied to theskin;

c. delivering sound or ultrasound energy from the applicator to the skinof the patient and through the skin of the patient to the nasal or sinusmucosa of the patient.

109. The method of clause 108 wherein the disease is an allergic diseaseand the sound or ultrasound overstimulates the nerves to inhibit theirfunction in the allergic disease.

110. The method of clause 108 further comprising delivering the sound orultrasound prior to, during, or after balloon sinuplasty.

111. The method of clause 108 wherein the sound or ultrasound comprisesfrequency between 50 Hz and 300 Hz.

112. The method of clause 108 further comprising delivering sound orultrasound just prior to, during, or after a functional endoscopic sinussurgery procedure.

113. The method of clause 108 wherein the sound and ultrasound isdelivered to the region of the external nasal nerve at the junction ofthe nasal cartilage and nasal bone.

114. The method of clause 108 further comprising delivering sound orultrasound just prior to, during, or after delivery of a bioactivematerial into the nasal cavity.

115. A method of creating tears in a patient comprising:

a. gripping a device with one hand and applying it to provide forvibration at 100 to 300 Hz with an approximately linear excursion of thetip of the device of about 500 to 1500 microns;

b. applying the device to the region of the external part of the nosewhere the nasal cartilage meets the nasal bone;

c. activating the external nasal nerve.

116. The method of clause 115 further comprising applying a force ofabout 0.5 N to about 3.0 N to the external nasal nerve.

117. The method of clause 115 further comprising applying a force ofabout 0.5 N to about 5.0 N.

118. A device to apply vibrational energy to an eyelid of a patientcomprising:

a. a handheld implement adapted to interface with an eyelid of an eye;

b. a retractor component connected to the handheld implement;

c. a sliding element adapted to slide along the retractor;

b. at least one piezoelectric element on at least a portion of theretractor element or the sliding element;

c. at least one temperature measuring element coupled to the retractorelement, the sliding element, or both;

d. a processor configured to adjust temperature based on the temperaturemeasuring element to maintain the temperature of the eyelid to about 39C to 50 C.

e. a power supply.

119. The device of clause 118 wherein the handheld implement furthercomprises a linear resonant actuator configured to vibrate the interfaceof the retractor or the sliding element coupled with the eyelid at afrequency of between 100 Hz and 400 Hz.

120. The device of clause 119 wherein the linear resonant actuator, thepiezoelectric element, and the pressure are applicable independently ortogether to treat dry eye.

121. The device of clause 118 wherein the processor is configured tosupply a current to the piezoelectric element to oscillate thepiezoelectric element at a frequency of between 1 MHz and 5 MHz

122. The device of clause 118 wherein the handheld implement furthercomprises a region on the implement through which manual pressure can beapplied to the eyelid.

123. The device of clause 122 wherein the region is a compliant region.

124. The device of clause 118 wherein the processor is electricallycoupled to the temperature measuring element.

125. The device of clause 118 wherein said distal end of said implementis adapted to retract an eyelid.

126. The device of clause 125 wherein said distal end of said implementis comprised of a hydrogel coating.

127. The device of clause 125 wherein said distal end of said implementis comprised of a biocompatible silicone coating.

128. The device of clause 118 wherein said distal end of said implementis comprised of a PTFE coating.

129. The device or clause 118 wherein said sliding element is coupled toa strain gauge operative to measure pressure applied to the eyelid whenthe sliding element is in its operative position against the eyelid.

130. The device of clause 118 wherein said sliding element is coupled toa strain gauge operative to measure pressure applied to the eyelid whenthe sliding element is in its operative position against the eyelid andto further signal to the user that the strain and pressure have reacheda pre-specified limit.

131. The device of clause 118 further comprising a base control unit

132. The device of clause 118 wherein said distal end comprises at leastone thermistor to contact the inner eyelid when said eyelid isretracted.

133. The device of clause 118 further comprising a control box, saidcontrol box comprising digital controls to set at least one oftemperature range, amplitude, duty cycle of the ultrasound, and numberof active piezoelectric elements.

134. The device of clause 118 wherein the power supply is rechargeableand incorporated within a hand grip, the hand grip operatively attachedto the device.

135. The device of clause 118 wherein the distal end of said implementis further configured to allow for pressure to be applied to an eyelidthrough the implement, the pressure applied to the eyelid by pressurefrom the operator of the implement compressing the lid through acompliant portion of the implement.

136. The device of clause 135 wherein the compliant portion comprises aflexible membrane.

137. The device of clause 135 wherein the compliant portions comprisesan elastomer. 138. The device of clause 135 wherein the compliantportion further comprises a pressure sensor.

139. The device of clause 135 wherein the temperature measurementelement comprises an infrared sensor.

140. The device of clause 135 wherein the temperature measurementelement comprises a thermistor.

141. The device of clause 118 wherein the temperature measurementelement collects data used in a model to predict temperature within theeyelid.

142. The device of 141 wherein the temperature prediction is utilized tocontrol the on-off timing of the implement.

143. The device of clause 118 wherein the implement further comprises avibratory actuator with a preset or adjustable frequency and anamplitude.

144. The device of clause 118 wherein the implement is further adaptedto be depressed against the skin of an outer eyelid.

145. The device of clause 118 wherein the piezoelectric element deliversultrasound energy between 1 and 30 MHz

146. The device of clause 118 wherein the piezoelectric element deliversultrasound energy to the eyelid between 2 and 10 MHz

147. The device of clause 118 wherein the piezoelectric element isconfigured to deliver ultrasound energy to the Meibomian Glands.

148. The device of clause 118 wherein the piezoelectric element isconfigured on the implement to deliver energy through the eyelid fromoutside the eyelid.

149. A device to apply heat to an eyelid comprising:

a. a handheld implement adapted to interface with an eyelid of an eye;

b. at least one piezoelectric element;

c. at least one temperature measuring element; and

d. a processor configured to adjust temperature based on the temperaturemeasuring element and a model which predicts the temperature inside aneyelid based on the temperature measuring element to maintain thetemperature of the eyelid within a safe range.

150. The device of clause 149 wherein the temperature measuring elementis an infrared sensor.

151. The device of clause 149 wherein the temperature measuring elementis an ultrasound detector.

152. The device of clause 149 wherein the temperature measuring elementis a thermistor.

153. The device of clause 149 wherein a processor is adapted to receivean input from the temperature measuring element and provide feedback tothe piezoelectric element to control temperature of the device.

154. The device of clause 149 further incorporating an integrated eyelidretractor.

155. A method to treat dry eye comprising:

a. applying a vibrating implement to a region proximate an eyelid ornose of a patient;

b. determining a set of test vibration parameters of the implement;

c. determining a location and optimal range of vibration frequency andamplitude of the implement based on patient and operator feedback;

d. setting the vibration frequency and amplitude of the implement basedon the patient and/or operator feedback.

156. The method of clause 155 wherein the implement further comprisesultrasound with frequency between 1 MHz and 30 MHz and the optimalfrequency is determined by the patient/user.

157. The method of clause 155 wherein the location is set to the regionwhere the nasal bone meets the nasal cartilage.

158. The method of clause 157 wherein the user further depresses theskin on the side of the face opposite the side where the implement isbeing applied.

159. The method of clause 159 wherein the user depresses the skin on thenose on the side opposite the placement of the implement and depressesthe implement simultaneously to transmit vibrations and activate nerveson both sides of the face.

160. The method of clause 155 wherein the location is proximate aninfra-orbital nerve.

161. The method of clause 155 wherein the location is proximate to asphenopalatine ganglia.

162. The method of clause 155 where the location is proximate anethmoidal nerve.

163. The method of clause 155 wherein the location is a lacrimal gland.

164. The method of clause 155 wherein the location is an accessorylacrimal gland.

165. The method of clause 155 wherein the location is the skin of theeyelid and the amplitude and frequency are chosen to eliminate outwrinkles it the eyelid.

166. The method of clause 155 wherein the vibration frequency is chosenfrom a frequency between 50 Hz and 300 Hz; and the amplitude is chosenfrom about 0.1 mm to about 1.5 mm; and wherein the amplitude issinusoidal; and wherein the implement moves with a substantially linearmotion.

167. A device to apply pressure and energy to the lid of an eyecomprising:

a. a first shaft adapted to pull a lid away from the sclera and corneaof a patient by gripping the inside of the eyelid;

b. a second shaft operatively connected to the first shaft adapted toapply pressure to the outside of the eyelid and compress the eyelidagainst the first shaft; and

c. an energy source located on the device operative to transmit energyto or from the eyelid through at least one of the first shaft and secondshaft.

168. The device of clause 167 further comprising a vibratory elementmechanically coupled to at least the first shaft and/or the secondshaft.

169. The device of clause 167 further comprising an ultrasound elementon the first and/or second shaft.

170. The device of clause 167 comprising a mechanism to apply pressureto the eyelid between the first shaft and the second shaft; and, adevice which transduces vibration to the first and/or second shaft andthence to the eyelid.

171. The device of clause 167 further comprising at least one ultrasoundelement which generates ultrasound within a frequency range of about 1MHz to about 15 MHz

172. The device of clause 167 further comprising a temperature sensingelement.

173. The device of clause 167 wherein the first shaft and the secondshaft are connected by a member said member comprising an elasticmaterial attached between the first shaft and second shaft, said elasticmaterial creating tension on the first and second shaft as the shaftsmove relative to one another.

174. The device of clause 167 wherein a housing surrounds the first andsecond shaft said housing comprising a compartment for a portablebattery.

175. The device of clause 167 wherein electrical connections aretunneled through the shaft to reach the region of the device whichcontact the eyelids of the patient.

176. The Device of clause 167 wherein the energy source is at least onelight emitting diode.

177. The device of clause 167 wherein the energy source is at least onelight emitting diode which generates radiation in the wavelength rangegreater than 500 nm.

178. The device of clause 167 wherein the energy source operates totransfer energy from the eyelid to cool the eyelid.

179. The device of clause 167 wherein the

180. The device of clause 167 further comprising at least onetemperature sensor.

181. The device of clause 167 wherein the first shaft and the secondshaft are operatively attached through an elastic connector.

182. The device of clause 167 wherein the first shaft and the secondshaft are operatively attached through an elastic connector and theexcursion of one shaft relative the other shaft is quantitated throughwith a sensor which detects strain or incremental movement.

183. The device of clause 167 further comprising 184. A device to applyenergy to the inside of the eyelid comprising:

i. a distal tip configured to retract the eyelid; and

ii. an energy source attached to the distal tip.

185. The device of clause 184 wherein the distal tip comprises anultrasound energy source.

186. The device of clause 184 wherein the distal tip comprises avibratory energy source which vibrates at between 50 and 400 Hz and anamplitude of between 500 microns and 3 mm.

187. The device of clause 184 wherein the distal tip comprises a seconddistal tip, mechanically coupled to the first distal tip in whichpressure can be applied to the eyelid.

188. The device of clause 184 wherein the distal tip further comprises asuction apparatus, said suction apparatus configured to retract the lidaway from the sclera of the eye whenst said energy source can beapplied.

189. The device of clause 184 wherein the distal tip further comprises asuction apparatus configured to pinch the skin of the eyelid and applyenergy through the pinched skin.

190. The device of clause 184 wherein the distal tip comprises graspersthrough which energy is applied to the eyelid when the skin of theeyelid is pinched.

191. The device of clause 184 wherein the device comprises a distal tipand said distal tip is configured to have a retractor to mechanicallyretract the eyelid from the sclera of the eye.

192. The device of clause 184 wherein the distal tip is configured tohave a retractor to mechanically retract the eyelid

193. The device of clause 184 wherein the distal tip is configured tohave a retractor to mechanically retract the eyelid and the distal tipis further configured to have an ultrasound element on the mechanicalportion which retracts the eyelid.

194. The device of clause 184 wherein the distal tip is configured

195. A method to create tears and secretions from Meibomian glandscomprising:

a. retracting an eyelid of a patient;

b. visualizing the mucocutaneous junction of the eyelid;

c. locating a device proximate to the eyelid; and

d. activating the device to apply transmit mechanical vibration from theend effector of a device to the mucocutaneous junction.

196. A method to generate tears in a human subject comprising:

a. applying an applicator to an external region of a nose of a subject,the region located where the external branch of the anterior ethmoidalnerve exits to the skin alongside the nose; and

b. activating the applicator to generate mechanical vibration at afrequency of between 100 and 300 Hz, the vibration generating a force onthe skin and underlying nerve sufficient to activate the nerve.

197. The method of clause 196 further comprising: actively mappingnerves in the skin distributions on the face of a subject to determinethe optimum location for stimulation of the exterior anterior ethmoidalnerve.

198. The method of clause 197 wherein the active mapping comprisesstimulating the nerves in the skin distributions on the face of thesubject with a range of frequencies of between 50 Hz and 300 Hz, a rangeof amplitudes between 0.5 mm and 3.0 mm and a range of forces between0.5 N and 3 N.

199. The method of clause 197 wherein the active mapping furthercomprises monitoring the effect of the stimulation of the nerves.

200. The method of clause 199 wherein the active mapping comprisesmonitoring one of: tearing, sneezing, and itching.

201. The method of clause 197 further comprising determining one of:optimum frequency, position, force, amplitude, duration, power, and dutycycle

202. The method of clause 199 further comprising: positioning theapplicator specifically along the mapped regions.

203. A method to generate tears in a human subject comprising:

a. applying an applicator to an external region of a nose of a subject,the region located where the external branch of the anterior ethmoidalnerve exits to the skin alongside the nose;

b. activating the applicator to generate mechanical vibration at afrequency of between 50 Hz and 300 Hz; and

c. applying a force over an area of about 1 mm² to about 5 mm² on theskin and underlying nerve of approximately 0.5 N to about 2 N toactivate the nerve.

204. The method of clause 203 further comprising 205. A deviceconfigured to activate tears in a human patient comprising:

a. an end effector configured to interface with the external skin overthe region of the nose where the external nasal nerve exits the nasalbone;

b. a main body configured to be handheld; and

c. an actuation mechanism coupled to the end effector and configuredproduce mechanical vibration of the end effector.

206. The device of clause 205 wherein the end effector is configured toapply 0.5 N to 3.0 N force over an area of about 1 mm² to about 5 mm².

207. The device of clause 205 wherein the end effector comprises an edgewith and edge radius of curvature of 0.5 mm to 2.0 mm.

208. The device of clause 205 wherein the end effector comprises a notchto fit in the region of the interface of the nasal cartilage and nasalbone.

209. The device of clause 205 wherein the end effector further comprisesa biocompatible material with a durometer between 20 A and 60 A.

210. The device of clause 205 wherein the end effector is actuated tomove a distance of between 5 mm and 30 mm.

211. The device of clause 210 wherein the end effector is actuated tomove a distance of between 5 mm and 30 mm while maintaining relativelyconstant force of between 0.5 N and 3.0 N.

212. The device of clause 205 wherein the actuator comprises a linearresonance actuator.

213. The device of clause 205 wherein the actuator comprises aneccentrically weighted motor.

214. The device of clause 205 wherein the actuator comprises a voicecoil.

215. The device of clause 205 wherein the actuator comprises anelectromagnet.

216. The device of clause 205 wherein the actuator comprises apiezoelectric crystal.

217. The device of clause 205 wherein the actuator is configured toaccelerate the end effector with a linear motion.

218. The device of clause 205 wherein the actuator is configured toaccelerate the end effector in a circular motion.

219. The device of clause 205 wherein the actuator is configured toaccelerate the end effector in a sinusoidal pattern.

220. The device of clause 205 wherein the actuator is configured toaccelerate the end effector in a programmable pattern.

221. The device of clause 205 wherein the actuator is configured toaccelerate the end effector in a pattern which is programmable with asmart phone application.

222. A method for treating rhinitis, comprising: delivering a vibratorystimulus via a probe to treat rhinitis in a patient in need thereof,wherein the probe is in contact with one or more tissues of the nose ofthe patient during delivery of the vibratory stimulus.

223. The method of clause 222, wherein the electrical stimulus isdelivered in response to one or more symptoms of rhinitis.

224. The method of clause 223, wherein the one or more symptoms ofrhinitis comprise one or more of itching, sneezing, congestion, runnynose, post-nasal drip, mouth breathing, coughing, fatigue, headache,anosmia, phlegm, throat irritation, periorbital puffiness, watery eyes,ear pain, and fullness sensation.

225. The method of clause 222, wherein the vibratory stimulus isdelivered more than once per day on a scheduled basis.

226. The method of clause 222, wherein the one or more tissues of thenose is the nasal mucosa.

227. The method of clause 222 wherein the one or more tissues of thenose is skin on the outside of the nose.

228. The method of clause 222, wherein the one or more nasal tissues isthe mucosa adjacent to the nasal septum.

229. The method of clause 222, wherein the vibratory stimulus is alinear motion with an oscillation frequency of about 100 to 300 Hz.

230. A method of treating rhinitis, comprising: delivering a vibratorystimulus to a nasal tissue of a subject to improve rhinitis of thesubject, wherein the vibratory stimulus is delivered via probecomprising a control subsystem to control the vibratory stimulus.

231. The method of clause 230, wherein the vibratory stimulus isdelivered in response to one or more symptoms of rhinitis.

232. The method of clause 231, wherein the one or more symptoms ofrhinitis comprise one or more of itching, sneezing, congestion, runnynose, post-nasal drip, mouth breathing, coughing, fatigue, headache,anosmia, phlegm, throat irritation, periorbital puffiness, watery eyes,ear pain, and fullness sensation.

233. The method of clause 232, wherein the vibratory stimulus isdelivered at least once daily during a treatment period.

234. The method of clause 232, wherein the vibratory stimulus isdelivered on a scheduled basis during the treatment period.

235. A method for treating ocular allergy, comprising: delivering avibratory stimulus via probe to treat ocular allergy in a patient inneed thereof, wherein the probe is in contact with nasal tissue of thepatient during delivery of the vibratory stimulus.

236. The method of clause 235, wherein the vibratory stimulus isdelivered in response to one or more symptoms of ocular allergy.

237. The method of clause 235, wherein the one or more symptoms ofocular allergy comprise one or more of swelling, puffiness, itching,tearing, and discharge.

238. The method of clause 235, wherein the nasal tissue is nasal mucosa.

239. The method of clause 235, wherein the nasal tissue is the externalskin of the nose.

240. The method of clause 235, wherein the vibratory stimulus is alinear motion at approximately 100 Hz to 300 Hz.

241. A method of treating ocular allergy, comprising: delivering avibratory stimulus to a nasal tissue of a subject to improve ocularallergy of the subject, wherein the vibratory stimulus is delivered by aprobe of a stimulator comprising a control subsystem to control thevibratory stimulus.

242. The method of clause 235, wherein the electrical stimulus isdelivered in response to one or more symptoms of ocular allergy.

243. The method of clause 236, wherein the one or more symptoms ofocular allergy comprise one or more of swelling, puffiness, itching,tearing, and discharge.

244. A method to treat narcolepsy comprising:

a. Positioning a vibratory surface at a bony region on the patient'sface communicating with a parasympathetic nerve;

b. Vibrating the vibratory surface at a frequency and a displacementselected to stimulate the external nasal nerve.

245. A method to treat epilepsy comprising:

a. Positioning a vibratory surface at a bony region on the patient'sface communicating with a parasympathetic nerve;

b. Vibrating the vibratory surface at a frequency and a displacementselected to stimulate the external nasal nerve.

246. A method to treat headaches comprising:

a. Positioning a vibratory surface at a bony region on the patient'sface communicating with a parasympathetic nerve;

b. Vibrating the vibratory surface at a frequency and a displacementselected to stimulate the external nasal nerve.

247. A method to treat sinusitis comprising:

a. Positioning a vibratory surface at a bony region on the patient'sface communicating with a parasympathetic nerve;

b. Vibrating the vibratory surface at a frequency and a displacementselected to stimulate the external nasal nerve.

248. A method to treat rhinitis comprising:

a. Positioning a vibratory surface at a bony region on the patient'sface communicating with a parasympathetic nerve;

b. Vibrating the vibratory surface at a frequency and a displacementselected to stimulate the external nasal nerve.

INCORPORATION BY REFERENCE AND PRIORITY CLAUSES

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended clauses. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts and ultrasound probe in proximity to an eyelid.

FIG. 2 depicts an ultrasound adjunct inside an eyelid.

FIG. 3 depicts a tear duct with inspissated material.

FIG. 4 depicts a retractor inside an eyelid.

FIG. 5 depicts a retractor with heating elements on it and a control box

FIG. 6 depicts a method to treat eyelids with ultrasound

FIG. 7 depicts another embodiment of a transducer and ultrasound adjunctcoupled together.

FIG. 8 depicts simultaneous ultrasound probes applying ultrasound to theocular tissues.

FIG. 9 depicts a retractor for the eyelid with an ultrasound elementpresent on the tip in contact with the lower eyelid.

FIG. 10 depicts a contact lens which responds to the therapeuticultrasound.

FIG. 11 depicts a multi-element array at the end of an ultrasound probe.

FIG. 12 depicts a set up of ultrasound transducer to deliver focusedultrasound energy to the back of the eye.

FIG. 13 depicts a device to deliver vibrational energy to the nasalturbinates and nerves inside the nasal cavity via contact through theskin and bony structures of the nose.

FIG. 14 depicts a coronal section through the sinuses

FIG. 15 depicts a coronal section through the face with the tear ductanatomy outlined.

FIG. 16 illustrates an ultrasound transducer adapted to apply ultrasoundenergy to the tissues of the nasal cavity.

FIG. 17 depicts the interface between an ultrasound device and thetissues of the face.

FIG. 18 depicts a coronal view of the sinuses.

FIGS. 19 and 19A-21 depict variations of the end effector of a devicedesigned to apply vibrational energy to the head and neck.

FIGS. 22-23 depict devices and simulation of devices to apply focusedultrasound to the retina.

FIG. 24 depicts a graph of clinical data related to frequency vsresponse.

FIG. 25 depicts a handheld device to apply pressure and heat to theeyelid.

FIG. 26 depicts a view of a handheld device to apply energy to theeyelid.

FIG. 27 depicts a close-up of a handheld device to apply ultrasound toan eyelid.

FIG. 28 depicts an exploded view of a handheld device to apply severalforms of energy to the eyelid.

FIG. 29 depicts an assembly schematic for a device to apply vibratingenergy to nerve trigger points on a face.

FIG. 30 depicts the boney and soft tissue structures in and around thenose.

FIG. 31 depicts the nerve anatomy in and around the nose.

FIG. 32 depicts an embodiment of a tear stimulator

FIG. 33 depicts a detailed drawing of a teat stimulator

FIG. 34 depicts an embodiment of a handheld tear stimulator.

FIG. 35 depicts an expanded view of a handheld neurostimulator to createtears.

FIG. 36 depicts an expanded view of a neurostimulator device.

FIG. 37 depicts an expanded view of another neurostimulator device.

FIG. 38 depicts another embodiment of an external nasal neurostimulator

FIG. 39 depicts a schematic of the inner workings of the device shown inFIG. 38.

FIG. 40 is an exploded view of FIG. 39.

FIG. 41 is an embodiment in which vibration is applied to the lateralaspect of the nose.

FIG. 42 is detailed schematic of the device in FIG. 41.

FIG. 43 depicts a device which applies mechanical vibration bilaterallyto a patient.

FIG. 44 depicts the device in FIG. 43 in more detail.

FIG. 45 depicts the inner mechanism of a device to create tears in apatient

FIG. 46 depicts the inner mechanism of a device to create tears in apatient.

FIG. 47 depicts a device which generates linear vibratory motion to beapplied to the skin of the face of a patient.

DETAILED DESCRIPTION OF THE INVENTION

The inventions contained herein all pertain to utilizing mechanicalforce to treat disorders of the eye including disorders of the front ofthe eye and the back of the eye.

Sound and Ultrasound and vibration are utilized interchangeably in thisinvention description. Mechanical vibration at audible frequencies (20to 20,000 Hz) may or may not actually transmit audible sound waves butmay transmit force to a surface and is included in the broad definitionof sound and ultrasound. Vibration, or mechanical vibration, is thebroadest term and encompasses all sound or ultrasound regardless ofwhether pressure waves are created. Sound is simply mechanical vibrationwhich transmits pressure waves through a medium which is then processedand “heard.” Vibration as a category encompasses ultrasound and sound aswell as mechanical vibration which may not result in sound. For example,mechanical vibration may be delivered by a probe with a linear motion, aplanar motion, or motion in all three axes. The important aspect ofmechanical vibration is the motion and a frequency of at least a fewHertz (Hz). The underlying mechanism of purposeful vibration (as opposedto unwanted vibration created incidentally to another mechanism such asa running motor) is to and from motion intentionally created by a movingmechanism along with transduction to another medium, for example, a bodytissue of a human subject. The motion of the vibration can be created bya number of different mechanisms including motors with a gear andcamshaft to create an offset, an eccentric motor, a linear resonantactuator, a voice coil, and a piezoelectric mechanism. In this respect,mechanical vibration is easier to create than sound.

The frequency of the sound waves may range from the low frequency subaudible range to the higher frequency inaudible ultrasound range. Onedevice of the current invention preferentially reflects ultrasound atthe inner surface of the eyelid to direct the heat to the inner portionof the eyelid while substantially preventing the heat from conducting tothe eyeball. Another device is a retractor for the eyelid to pull theeyelid from the surface of the eye while applying the heat through theretractor. One method further enhances opening of the glands within theeyelid by combining the therapy with bioactive materials or genedelivery molecules on the inside of the gland. In other embodiments,therapeutic ultrasound is utilized to open the blood retinal barrier andallow gene and drug therapy with large molecules. In other embodiments,therapeutic ultrasound is utilized to create changes to the anteriorportion of the eye. Methods and devices are also described which allowheat to safely be applied to the eyelid of an eye utilizing ultrasoundpassed through the eyelid. One device preferentially reflects ultrasoundat its surface to direct the heat to the inner portion of the eyelidwhile substantially preventing the heat from contacting the eyeball.Another device retracts the eyelid from the surface of the eye whileapplying the heat and optionally applies a controlled amount ofpressure, ultrasound, and mechanical vibrations. Another device appliescavitating ultrasound through the eyelid to enhance opening of theglands within the eyelid. One method further enhances opening of theglands within the eyelid by combining the therapy with bioactivematerials on the inside of the gland.

Other devices treat dry eye by increasing the amount of tears in theeye. These devices act synergistically with devices which improve thequality of the tear film. These devices create tears by activating thesphenopalatine ganglion (indirectly or directly) and/or facial nervebranches, and/or ethmoidal nerves with ultrasound or sound or mechanicalvibration externally applied through the skin of the nose. An example ofa direct stimulation of the sphenopalatine ganglia is throughstimulation of the ganglia itself. An example of indirect stimulation ofthe sphenopalatine ganglia is through activation of a sensory pathwaywhich then communicates via reflex neural circuit to the sphenopalatineganglia to increase output or tears. Another embodiment can treat avariety of disorders utilizing sound and/or ultrasound and/or vibrationwhich is externally applied to the skin of the head and neck andactivates nerves or nerve ganglia under the skin. Another embodimentapplies vibratory energy to the mucosa inside of the nose or to themucosa on the inside of the eyelids to treat dry eye.

The retinal blood vessels communicate with the cerebral blood vessels;access to the cerebral blood vessels also provides access to the bloodvessels of the retina. According to one embodiment of this invention, amethod and apparatus are provided to enhance delivery of therapeuticmolecules across the blood brain barrier by stimulation of thesphenopalatine ganglia (SPG) and/or its outgoing parasympathetic tractsand/or another parasympathetic center; stimulation of the SPG has beenshown to control the several important blood brain barrier effects [e.g.see Levi et. al. Stimulation of the Sphenopalatine Ganglion InducesReperfusion and Blood-brain Barrier Protection in the PhotothromboticStroke Model; PLoS One 2012; 7(6)]. Importantly, the method andapparatus stimulate the SPG through an external device, activatingnerves close to the skin of nasal region which are connectedbiologically through a neural network or can be directly activated withvibration through the skin. The apparatus typically stimulates theparasympathetic nerve fibers of the SPG directly or indirectly, therebyinducing the middle and anterior cerebral arteries to dilate, and alsocausing the walls of these cerebral arteries walls to become morepermeable to large molecules. In this manner, the movement of largepharmaceutical molecules from within blood vessels to the cerebraltissue is substantially increased. Preferably, therefore, this methodcan serve as a neurological drug delivery facilitator, without thesacrifices in molecular weight required by techniques of the prior art.In general, it is believed that substantially all pharmacologicaltreatments aimed at cerebral cells for neurological and psychiatricdisorders are amenable for use with these embodiments of the presentinvention. In particular, these embodiments may be adapted for use inthe treatment of disorders such as brain tumors, epilepsy, Parkinson'sdisease, Alzheimer's disease, multiple sclerosis, schizophrenia,depression, stress, anxiety, and any other CNS disorders that aredirectly or indirectly affected by changes in cerebral blood flow or byBBB permeability changes.

In other embodiments, the SPG is stimulated as an acute treatment formigraines, cluster headaches, epilepsy, Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, schizophrenia, depression, stress, anxiety,obsessive compulsive disorder, tremor, sinusitis, vasomotor rhinitis,allergic rhinitis, common (viral) cold, allergic conjunctivitis,glaucoma, xerostomia (dry mouth), and nasal polyposis.

The nasolacrimal apparatus is the physiological system containing theorbital structures for tear production and drainage. It consists of thelacrimal gland, the lacrimal canaliculi, and the nasolacrimal duct whichcommunicates with the cavity of the nose. The innervation of thelacrimal apparatus involves both the sympathetic supply through thecarotid plexus of nerves around the internal carotid artery, andparasympathetically from the lacrimal nucleus of the facial nerve in thebrainstem. Signals travel from sensory (afferent) fibers around the faceto the area of the salivary nucleus in the brainstem to activate theparasympathetic fibers which travel back to the sphenopalatine gangliato synapse and then send terminal nerve fibers to innervate the lacrimalgland.

In one embodiment (FIG. 1), a device 110 is presented in which vibrationor sound or ultrasound is applied directly to an eyelid 100 of apatient. The applied ultrasound may be in the low frequency range orhigher frequency range; typically, low frequency ultrasound begins atabout 20,000 Hz and higher frequency ultrasound begins around 500,000 Hzand up to even 100 MHz. In some embodiments, audible sound is alsocapable of delivering energy to the eyelid and for some applications, ispreferred. Therefore, the range of sound delivered to the eyelid is fromabout 50 Hz to about 100 MHz. In some embodiments, it's directmechanical movement of an interface which stimulates tear production. Insome embodiments, different frequencies are used alone or in combinationwith one another. In some embodiments, higher frequencies are used inimaging and lower frequencies for therapy, each independently or incombination. Ultrasound can be applied by the device to the inner eyelid100 and the ultrasound energy can travel through the inner eyelid 100.In some embodiments, vibration is utilized in combination withstimulation with electrical current.

As the ultrasound travels through the eyelid, in some embodiments, theultrasonic waves vibrate structures such as tear ducts and Meibomianglands 130 (FIGS. 2-3), specifically tear ducts which may containinspissated oils, or are otherwise blocked with material 135 (FIG. 3)preventing tears or tear components (e.g. oils, lipids, etc.) from beingexcreted into the tear film 160 of the eye. In one example, a diseasewhich is treated is dry eye.

In another embodiment, eyelash growth is stimulated with mechanicalvibration. For example, it has been shown in previous models in bonetissue that ultrasound delivered at 50 kHz and 1 MHz stimulatesprostaglandin release (Bone 2002 Jul. 31; 236-41). Prostaglandin releasehas been considered the main mechanism of action for the pharmaceuticalagent bimatoprost, an FDA approved agent to stimulate eye lash growth.Therefore, in one embodiment, a vibratory stimuli is utilized toupregulate prostaglandin synthesis and increase thickness of eyelashesin a subject. Indeed, any of the embodiments herein may be combined withpharmaceuticals.

Device 110 may be applied to the upper eyelid or the lower eyelid insome embodiments. In some embodiments, ultrasound devices are applied toboth lids simultaneously. As described herein, device 110 may generateultrasound, sound, or predominantly vibrate at high amplitude at lowerinaudible frequencies (e.g. 100-300 Hz). Vibration may occur at Device110 in some embodiments has a programmable frequency and in someembodiments, a programmable amplitude. Device 110 in some embodimentshas a wettable (e.g. hydrogel) end in which a contact with the skin ofthe eyelid is facilitated (skin interface). In some embodiments, asilicone, or rubber skin interface is used. In some embodiments,microbubble or pharmaceutical adjuncts are added to the eyelid tofacilitate disruption of the inspissated material and ultrasound canfacilitate the distribution of the pharmaceuticals into the glands andlids. For example, a steroid or detergent can be introduced into theglands to facilitate break up of inspissated ducts and vibration appliedto further enhance the effect of the pharmaceutical or chemical agents.

FIG. 2 depicts an inner lid 150 and a Meibomian gland 130 with material135 blocking the duct (FIG. 3). Ultrasound, sound, or vibration can beused to heat and/or vibrate the material 135 to remove it from the duct130 (FIG. 3). Preferably, the ultrasound frequency chosen is one whichresonates at the interface of the duct and the inspissated material todislodge or heat the material in the duct so that the secretions fromthe duct can reach the eye and prevent dry eye. For example, early workhas shown that sound frequencies in the 100 Hz to 500 Hz range will leadto break up of the material in the inspissated ducts. When combined withhigher frequency ultrasound energy (e.g. 1 MHz to 3 MHz), the materialcan be heated to improve the efficiency of the unblocking of the ducts.In some preferred embodiments, temperature measurement is utilized tofacilitate the safety and efficacy of the treatment; a temperature rangeof between 40 and 48 Celsius is the preferred temperature. Thetemperature can be controlled with closed loop control in which athermistor is utilized to measure temperature and then the feedbackthrough a control circuit is utilized to control the power output so asto maintain the temperature in a pre-specified range. In one embodiment,an ultrasound adjunct 170 (FIG. 2) is utilized to augment the ability ofthe ultrasound to heat the inner portion of the eyelid and protect theeye. In one embodiment, the adjunct 170 contains an interface whichreflects ultrasound heat at the region of the interface between theadjunct and the inner portion of the eyelid 150. In one embodiment, thisadjunct is stainless steel or other metal and is good reflector ofultrasound so that heat is generated at the interface with the glandsand not at the surface of the cornea. The adjunct can be any materialwith an interface which reflects ultrasound such as a balloon with a gasinside. Ultrasound is reflected at interfaces and the interface createdat the region of the adjunct is transmitted to the inner portion of theeyelid while the eye is protected. Heating will occur at the interfaceof the adjunct 170 and the eyelid. The adjunct in some embodimentscontains an air interface which is particularly adept at reflectingultrasound away from the sclera and to the inner portion of the lid 130.In another embodiment, the adjunct contains microbubbles which cavitateand can generate miniature shockwaves to dislodge the inspissatedmaterial.

In one embodiment, a method is described in which the lower eyelid isretracted inferiorly by a retractor 500 like device (FIGS. 4-5). Theretractor 510 serves three or four purposes in this embodiment: thefirst is that of a retractor to hold the eyelid back to prevent contactwith the eyeball; the second can be to act as a backstop to createpressure; the third can be to simultaneously deliver sound, ultrasound,and/or or vibratory waves 560 to the lid; and the fourth can be to actas the adjunct 520 for ultrasound. In this method, the vibration can bedelivered through the retracting device 510 and then through the eyelid515 to the inspissated ducts. In another embodiment, the retractorcontains heating and/or vibratory elements thereon 555; for example,piezoelectric devices 560 can be directly attached to one the innerportion of the retractor 510 (FIGS. 4-5). In this embodiment, one ormore thermistors 555 can also be added which measure temperature and acontrol loop can be utilized to maintain the temperature constantbetween about 40 and 45 degrees C. to both facilitate treatment andmaintain a safe zone for safety. In another embodiment, the temperatureis maintained between 38 C and 48 C, or in a narrower range between 42 Cand 44 C. In some embodiments, element 555 is a compliant material whichenables the user of the device to apply manual pressure to the eyelid.For example, element 555 is a gel, balloon, or other soft and compliantmaterial which is depressed by the operator of the device. The device500 has a handle 550 with a curve which enables the user to apply thedevice to the eye comfortably from a distance.

In another embodiment, cooling is employed to change the profile of theinspissated lipids to then facilitate change in phase and removal. Forexample, the inspissated lipid can be cooled or frozen so that itretracts in the ducts and are easily broken up by pressure, vibration,sound, or ultrasound. A cooling element 555, 560 might be athermo-electric type cooling element or a peltier effect cooler. Coolingmay be combined with sound and ultrasound.

Control box 570 contains software and hardware or software controls tocontrol temperature as well as to allow user facilitated parametercontrol. For example, the temperature 574 can be adjusted, duty cycle ofpower on and off 572, maximum power 578, and activation of one or morepiezoelectric elements 576 on the retractor 510. Retractor device 510can incorporate both vibratory, lower frequency, and higher frequencyultrasound with different controls for each to be applied independentlyor simultaneously. For example, in one embodiment, element 520 deliversultrasound at between 1 and 30 MHz while a vibratory frequency isapplied to the retractor at between 50 and 500 Hz, both mechanicalvibrations and ultrasound acting synergistically to dispel oils andunblock inspissated glands. These modes may be combined with electricalstimulation to enhance their effects. Electrical stimulation wouldpreferably be performed with a bipolar electrode on the portion of thedevice which contacts the inside of the eyelid.

In one preferred embodiment, the device 500 is completelyself-contained. That is, the power supply, the ultrasound, theelectronics, etc. are all contained within a handheld device and thereis no separate or external control box to control the individualelements. A control loop between the ultrasound transducer and the skinor the conjunctiva is utilized to maintain the temperature within aconstant range of about 40 C to 46 C.

In one preferred embodiment, a compliant region 555 is added to theretractor such that the compliant material can be depressed against theinner part of the retractor to apply direct pressure to the outside ofthe lid. The compliant region allows the user of the retractor tosimultaneously apply mechanical pressure to the eyelid while heat andvibratory energy are being applied. The compliant regions in oneembodiment takes the form of silicone inside a protective membrane. Inanother embodiment, the compliant region is a balloon fillable withfluid or air. The goal of the compliant portion of the retractor is toenable application of about 5 to 25 psi to the eyelid before, during, orafter treatment with the energy. Therefore, in one preferred embodiment,retractor 510 contains ultrasound, mechanical vibration, and mechanicalpressure elements to facilitate clearing of the ducts inside an eyelid.The pressure is preferably quantified in preferred embodiments of device500.

FIG. 6 depicts a method 600 to apply ultrasound to the inner portion ofthe eyelid to clear inspissated ducts on the inner portion of the lid.The lid is first retracted manually 610 or with a provided device 620.Another portion of the retractor is then applied to the outer portion ofthe eyelid to create pressure against the eyelid. Ultrasound is appliedvia transducer 620 to the inside of the eyelid with the outer deviceapplying pressure. In this embodiment, the ultrasound is transmitteddirectly from the transducer to the ducts of the inner eyelid.Optionally, a pharmaceutical or bioactive formulation is applied 630 toenhance the ultrasound effect or vice-versa. Optionally an elasticrecoil mechanism is included, both to measure the force or pressureapplied to the lids during ultrasound and heat application. Treatmentparameters 640 including time, energy level, sound frequency and dutycycle are applied to the transducer. The transducer is then powered on650 and the energy applied to the eyelid. In another embodiment of thedevice, the ultrasound transducers are placed on the outside of the ofthe retractor (e.g. FIGS. 26-27) such that the ultrasound travelsthrough the eyelid from outside to inside. The method of treatment issubstantially the same; however, when the transducers contact the outerskin of the lid, the design of the inner portion of the retractor whichcontacts the inner lid is freed up to maximize comfort for the patientand ease of use ability for the user of the system.

In another embodiment, the eyelid is not retracted and the device 620 isapplied over the eyelid to deliver the acoustic energy to the eye,either the inner or the outer eye. The energy travels through the eyelidand into the anterior chamber of the eye and should the power be enoughand the attenuation low, to the retina and back of the eye. Otherdiseases treatable with the retractor with this method includeconjunctivitis, bacterial conjunctivitis, glaucoma, maculardegeneration, and pterygia. For example, in one embodiment, anultrasound probe is applied over the eye to deliver vibratory energy tothe anterior chamber of the eye to open the trabeculae and allowimproved outflow of intraocular fluid to lower pressure. Experimentationpredicts that sound waves between 20 and 400 Hz leads to a lowerintraocular pressure. Ultrasound at higher frequencies, for example,between 1 MHz and 3 MHz will heat the ciliary bodies and decrease theproduction of intraocular fluid. Therefore, combining the two energylevels of vibratory energy (e.g. 200 Hz and 3 MHz) will actsynergistically to improve intra-ocular pressure.

In another embodiment (FIG. 7), an insulator (reflector of ultrasound toprotect eye) 1010 is placed inside the eyelid 1020 or on the eye 1000 toprotect or facilitate energy delivery via ultrasound 1030 during thetreatment. For example, a device adjunct might be a material that isplaced on the inner part of the eyelid or on the lid, the device adjunct1000 possessing the ability to prevent further propagation of ultrasonicwaves from the ultrasonic probe 1030 to enhance delivery of heat to theinner portion of the eyelid and protect the conjunctiva and sclera ofthe eye from the ultrasound and heat.

In one example, the device adjunct 1010 might consist of an outerportion and an inner portion, the two portions separated by a gas.Ultrasound does not travel through air well and therefore the ultrasoundwill be reflected from the device adjunct 1010, therefore effectivelyblocking the ultrasound from reaching the eye yet directing heat to theinner portion of the eyelid.

Furthermore, the interface at the point of internal reflections withinthe adjunct will begin to heat up as the ultrasonic waves arecontinually reflected from and within the device adjunct. In this methodof treatment, the device adjunct is applied to the inner surface of theeyelid and the ultrasound 1030 applied to the outer portion of theeyelid, the waves then transmitting through the eyelid to the Meibomianglands to break up the inspissation in the ducts.

In another embodiment depicted in FIG. 8, ultrasound transducer probes1220 are shown applying ultrasound to eyelids 1230 with a contact lens1210 underneath the eyelids 1230. The eye 1200 is protected by thecontact lens 1210 as well as additional ultrasound reflective layers onthe contact lens as described above and below.

In another embodiment, depicted in FIG. 9, the ultrasound transducer1400 and the ultrasound adjunct 1500 are coupled around the eyelid 1450.A reflective material or composite of materials 1550 can be furtherincluded in the coupled transducer-ultrasound adjunct. As in previousembodiments, the coupled transducer-adjunct surrounds the eyelid 1450and protects the eye 1600.

In another embodiment, a contact lens 1100 (FIG. 10) is applied to theeye and an ultrasonic energy probe 1110 is applied to the upper andlower eyelids while the eye is closed over the lens 1100. The lensprotects the cornea and can be produced such that the ultrasound energyis reflected back to the inner portion of the lid to heat and/ormechanically vibrate the inspissation out of the eyelid.

In another embodiment, ultrasound 1110 is utilized to deliverpharmaceuticals to the eyelids to treat dry eye syndrome. Ultrasound canenhance the delivery of many pharmaceuticals by enhancing their uptakeinto the cell membranes. In this method, in one embodiment,pharmaceuticals are applied to the inner eyelid of the upper or lowereyelid and subsequently ultrasound is applied to the eyelid to enhancethe delivery of the pharmaceutical to the eyelid.

For example, steroids or other anti-inflammatory medications,microbubble formulations, or other bioactive materials can be applied tothe inner lid, to a lid retractor, or to the ultrasound adjunct placedinside the lid. The bioactive material might further be incorporatedinto the ultrasound adjunct to, for example, slowly elute from theadjunct to the inner portion of the lid, the ultrasound furtheraugmenting its ability to interact with the glands within the eyelid. Inanother embodiment, an anti-inflammatory is applied to the lid orsurface of the eye and ultrasound utilized to enhance the uptake of theanti-inflammatory into the epithelial layers on the ocular surface.

In some embodiments, ultrasound is utilized to make alterations in thetissues of the eye. Tissues of the eye can include the eyelid, theeyebrow, the eyelashes, glands (for example lacrimal glands within andaround the eye) including Meibomian and lacrimal glands, any part of thesclera, the iris, the trabecular meshwork, the ciliary processes,Schlemm's canal, the retina and its different layer of cells, thechoroid, the vitreous, the lens, the lens capsule, the zonules, theaqueous humor of the anterior chamber, the optic nerve, the macula, thefovea, nerves which stimulate or inhibit processes in the eye (e.g.sphenopalatine ganglia, lacrimal nerve, trigeminal ganglia, facialnerve, ethmoidal nerves) and the retinal blood vessels including theretinal vein and artery and any branches.

Typical ultrasound (e.g. diagnostic imaging) is low intensity andutilizes reflections from tissues for imaging. If the power isincreased, then focused or unfocused therapeutic applications arise. Forexample, it is known that high intensity focused ultrasound can producehighly focal heating and lower intensity focal ultrasound can inducetissue regeneration. Low intensity and/or low frequency (e.g. 20 kHz to500 kHz) focused ultrasound can also be used for drug delivery byopening up cell membranes and allowing molecules to be transported intothe cells and tissues. Low intensity ultrasound applied to the oculartissues can result in a number of beneficial clinical results includinghealing of tissues such as the retina and drug and gene delivery to anystructure of the eye.

Ultrasound waves are created by resonating elements which producepressure waves at frequencies determined by the properties of theelements. In some applications, a single element is utilized and acurved shape of this element naturally focuses the ultrasound at a focalpoint. In another design 1120, for example FIG. 11, multiple elements1150, 1155 may be linked together, each with a phase control whichallows for focusing 1145 at a point distal 1165 from the array.Depending on the phase control, the focus point can be moved (electronicphasing). In some embodiments, the focused ultrasound is coupled to animaging device which simultaneously images structures in the eye andtransmits coordinates to the therapeutic ultrasound device to direct thetreatment. In some embodiments, the ultrasound waves remain unfocused orsoftly focused.

Referring to FIG. 8, a pair of ultrasound transducers 1220 are depictedin two different physical positions on the eye. Typically, theultrasound would be applied with the eye closed but in some embodiments,the ultrasound is applied with the eye open with the ultrasound probecontacting the conjunctiva. Each of the transducers is directed into theeye 1200 from different angles. In this embodiment, a pair oftransducers is depicted but the system may include a single transduceror more than two transducers depending on the application.

In some embodiments, it is preferred that the transducers are angled toavoid the lens such that minimal or no ultrasound energy reaches thelens because the lens can be very sensitive to heating and mechanicalforces. In this embodiment, the ultrasound beams overlap at a positionposterior to the lens. The exact position depends on the energy level,frequency, and the specific application of the ultrasound. Anotherreason that in some embodiments the transducers are offset from the lensis that the central visual pathway of the eye may be utilized forimaging of the intra-ocular structures such as, for example, if OCT werecouple to ultrasound or optical ophthalmic imaging (e.g. using a slitlamp).

Each of the transducers 1220 can create frequencies of ultrasound from10 kHz to 2 MHz depending on the application. In some embodiments,“ultrasound” isn't used and “sound” or “vibration” is used withfrequencies ranging from 10 Hz to 10 kHz. In this embodiment, anamplitude and frequency is specified. Each of the transducers can have amembrane or other acoustic coupling interface for the sclera or skin ofthe eye. The membrane 115 can be composed of a hydrogel or similarmaterial so it doesn't scratch or injure the scleral surface. In theembodiment where the ultrasound applicator is applied to the eyelid,then a membrane is not required and typical skin methods and materialsfor the ultrasound probe interface can be utilized. In some embodiments,the ultrasound transducers are configured into a patch or otherwise adevice which can be attached to the skin of a patient.

In one embodiment, the ultrasound transducers 1220 are placed on thesurface of the eye and coupled to one another to deliver focusedultrasound to the retina. By coupling the ultrasound transducerstogether, each of them can be made smaller in size. This arrangement isequivalent to having multiple elements yet the multiple elements areseparate in space so as to avoid sensitive structures such as the lens.The transducers 1220 can be coupled using optical coupling orelectromagnetic coupling or they can be coupled to each othermechanically or physically in space.

In some embodiments, a single ultrasound transducer can be used eitherdirected at an angle to the lens (pars plana) or directed straightthrough the cornea and lens to the posterior of the eye. In thisembodiment, the objective may be to softly focus the ultrasound or notfocus the ultrasound at all so that the retina or vitreous is exposed toa broad ultrasound field.

In some embodiments when a single transducer is used, the ultrasound iseither not focused or is focused softly or not focused at all. In anembodiment where the ultrasound is softly focused or not focused, thefocused ultrasound can have a maximum where a −6 dB radius around thecenter is within 2 mm, 4 mm, 6 mm, or 1 cm. If unfocused, the ultrasoundfocus extends to infinity and therapy occurs via a broad ultrasoundfield.

In some embodiments, ultrasound is applied to the posterior segment ofthe eye to loosen or break up fibrotic or avascular zones or lesions topromote drug delivery, healing, or both. Drug delivery to these lesionsmight include steroids, anti-angiogenic factors, or growth stimulants,and the like. Gene producing vectors may also be introduced in theposterior of the eye this way. The ultrasound to the posterior segmentmay be focused, softly focused, or unfocused depending on the desiredintensity and application and/or specificity of location. In someembodiments, the ultrasound is targeted at drusen, calcified lesions inthe retina, which can cause dry AMD or wet AMD in time.

“Floaters” are particulate matter in the vitreous portion in theposterior chamber of the eye; they are typically composed of bloodclots, congealed collagen, or other debris that break loose and causevisual distortions. In some embodiments, unfocused ultrasound can beutilized to break up this debris and improve vision. In thisapplication, the ultrasound probe is configured to apply a continuous orpulsed wave of unfocused ultrasound at a frequency (e.g. in the 10 Hz to800 kHz range) or the (100 kHz to 1 MHz) range so as to take advantageof the interface between the vitreous and the floater. In someembodiments, the vitreous is a gel and in this case, the viscous gel canbe broken up or liquefied to allow more free flow in the posteriorvitreous.

Clots can form in retinal veins or arteries just as they can in anyblood vessel in the body. In some embodiments, focused or unfocusedultrasound is used to break up these clots alone or in combination withthrombolytic agents or by itself without thrombolytic agents. In someembodiments, ultrasound sensitive microbubbles are delivered to thepatient intravenously and to the eye via circulation; ultrasound isapplied to the retina in either a focused or an unfocused manner towardthe retinal occlusion. Short bursts are delivered in some embodimentsand longer pulses are applied in other embodiments. In some embodiments,1 MHz ultrasound is utilized and in other embodiments, a range up to 30MHz is utilized depending on the desired penetration through the eye.

In another embodiment, a partial posterior vitreous detachment can becompleted using focused or unfocused ultrasound. The vitreous of theposterior cavity is typically tacked down to the retina. However, withage, the vitreous begins to separate. When it is only partiallydetached, it creates traction on the macula or other portion of theretina and there is both a need and a procedure to release the membranefrom the retina. However, these are dangerous procedures because oftheir invasiveness. Ultrasound can be non-invasively delivered. Macularholes or retina detachments can then form. Therefore, the vitreousshould be either completely detached or completely attached to theretina. Currently available treatments include treatment with an enzymewhich chemically disrupts the partial detachment to create a fulldetachment and relieve the stress on the retina or a vitrectomy (removalof the posterior vitreous and replacement with a similar liquid). Theuse of a non-invasive technology to relieve the distortion is likelypreferable and may be more effective than the standard treatmentmodality of either liquefaction or vitrectomy. Such non-invasivetechnology is also amenable to repeat treatments as well. In oneembodiment, unfocused ultrasound is applied to the eye through theeyelid or through conduction via the bony structures of the face.

FIG. 12 depicts a system 300 which generates ultrasound to deepstructures within the eye 100. Ultrasound transducers 312, 322 areconfigured to deliver ultrasound energy 18, 35, 311, 313 to structuresof the eye, e.g., the sclera 17, the surfaces of the cornea 14, 16, theiris 24, and an angle of the eye 26. One or more power amplifiers 306,310, 302 drive the ultrasound transducers to deliver the calculatedtherapeutic energy to the eye. In some embodiments, the ultrasoundtransducer 322 may serve as an imaging device which directs theultrasound from other ultrasound elements on the same transducer orelements on another transducer 312. CPU 308 directs the therapy.Processor 304 integrates signals from various components to create atreatment plan for an eye. Treatment region 318 is shown on the retinabut can in fact be anywhere in the eye; for example, the treatment canbe applied to the optic nerve, the sclera, the iris, the pupil, thelens, the trabecular meshwork, the cornea, lens capsule, theconjunctiva, the eyelids, Meibomian glands, eyelashes, orbital bones,blood vessel such as the retinal artery and veins, etc. The treatmentregion 318 can result from focused ultrasound being applied fromdifferent directions into the eye or can result from a singlepropagating ultrasound wave. The treatment region is defined byperpendicular line 32 which traverses the front of the eye as and itsperpendicular line 28 which can be used to direct the external therapye.g. through reflections.

Treatment line 30 is a line directly down the center of the eye, or justoff the center 19 of the eye and can serve as a reference point for thetreatment; in some embodiments, the ultrasound is delivered along thiscenter line of the eye to the retina or along a line parallel to it; drepresents an offset from the center line. In some embodiments, angletheta 21 is used to guide the position and orientation of therapeutictransducers 312, 322. Angle theta represents an angle to the center lineof the eye. If the center line of the eye is known and the distance fromthe front of the eye to back is known, then the angle determines theposition along the sclera to deliver the ultrasound energy to the retinaregion.

In another embodiment, ultrasound is applied to an eye simultaneously orin sequence with ionizing radiation therapy to enhance the treatment ofthe retina with the ionizing radiation.

In another embodiment, a tracking system for the eye is utilized for thetreatment with the ultrasound. In the tracking system, a fiducial is notutilized by the system. A three dimensional image of the eyeball isutilized, the image utilized to place the entire eye into a threedimensional coordinate reference frame. In another embodiment, a twodimensional B-mode image of the retina is utilized for tracking. Forexample, speckles on the retina ultrasound image can be used to trackmovement of the retina and update a location on the retina for treatmentwith therapeutic ultrasound.

In another embodiment, micropores are created using focused ultrasound.Micropores result from specific energy intensity being applied to theretina. Research suggests that the blood retina and the retina vitreousbarrier can be transiently interrupted using focused ultrasound. Thisinterruption can be utilized to allow for enhanced drug delivery. Inanother embodiment, the stimulating effect of ultrasound is utilized toenhance delivery of pharmaceuticals or gene delivery vectors. In oneexample, when a sub-retinal injection of a gene delivery emulsion isdelivered to the retina, ultrasound is utilized to enhance the deliveryafter the injection.

In another embodiment, bubbles or microspheres are used to open pores inthe retina for drug and gene delivery. The microbubbles create a smallcavitation region which can transiently open cells to enhance deliveryof bioactive agents to the region.

In another embodiment of the system to deliver ultrasound to thestructures of the eye, a treatment device in the form of an eye mask isutilized which covers both eyes and contains ultrasound transducerspointed toward the retina of the patient. The mask has a series ofultrasound transducers directed to the eye. The transducers may bearranged around the mask in a ring or on the edges of the mask todeliver the ultrasound energy at an angle 21 to the lens. The mask maycontain a single transducer for each eye or multiple transducers pereye. The size of each transducers might be under a millimeter (mm) orgreater than one mm and up to one cm. The electronic control circuitwhich turns the transducers on and off might alternate power to one ormore of the transducers to enable high power to be delivered to each ofthe transducers in an alternating manner so as to maximize the powerleaving each transducer at a given time.

In another embodiment, ultrasound is used to stimulate tear productionby a lacrimal gland in the eye. For example, ultrasound waves 1030 areapplied to the conjunctival region above the eyelid (FIG. 7) tostimulate the lacrimal gland to secrete tears. An ultrasound probe 1030is applied to the eyelid through which ultrasound is applied to thelacrimal gland. Unfocused ultrasound is utilized to stimulate thelacrimal gland through the eyelid. The energy level of the ultrasound atthe point the waves interact with the lacrimal gland is 1 mW/cm2 to 10W/cm2 at sonic frequencies 50 kHz to 30 MHz. In some instances, theultrasound is focused and in others, the ultrasound is unfocused. Theprobe is in the form of a wand which is held on the eyelid in the regionof the lacrimal gland. When ultrasound is applied the stimulating effectof the ultrasound stimulates the tear duct to release tears. In someembodiments, sound waves are used in place of ultrasound. Vibratingsound waves at (for example 50-300 Hz) can penetrate bone and stimulatenormal tissue by activating nerves.

It has also been determined that lower frequency (not sound) vibrationscan stimulate tear production. For example, vibration at a frequency of100 Hz or 300 Hz and up to 1 KHz can stimulate the anterior ethmoidalnerve, the sphenopalatine ganglia, the lacrimal nerve, the facial nervesand more internal nerves and ganglia otherwise accessible only byinvasive methods. For example, the lacrimal nerves or nerves proximal tothe lacrimal nerve such as the sphenopalatine ganglia, the ethmoidalnerves, the vidian nerve, and the infraorbital nerves can be stimulateddirectly through the application of vibratory energy through the skinand bones. The energy travels through the skin and meets the bone, atwhich point the bone resonates to produce stimulation of the nerves.Therefore, in one embodiment, a probe 1030 is applied to the uppereyelid and the probe delivers vibratory energy to the lacrimal gland,inducing immediate tear production.

In another embodiment, ultrasound transducers are applied to bonyregions of the face and in a preferred embodiment on the orbit region totransmit ultrasound to the posterior or anterior of the eye. Theultrasound is transmitted across the bones to the retina region byconduction through the bones. Therefore, in this method, vibration isutilized to stimulate the retina via vibration of the bony structures ofthe orbit and resultant resonant transmission to the retina.

In another embodiment, ultrasound is applied to the skin surface of theface to facilitate exit of infection from the Eustachian tube in otitismedia. In this example, the resonance of the bone agitates the infectedfluid inside the Eustachian tube to assist in its expulsion. In anotherembodiment, the device is utilized to maintain uniform pressure in theeustachian tube, for example, during aircraft travel, during SCUBAdiving, or in the case of sinusitis or a cold.

FIG. 13 depicts an embodiment of a device to stimulate the lacrimalgland or other nerves or ganglia transcutaneously through the skin tothe nerves and ganglia. Regions 2012, 2014, and 2010 have been shownexperimentally to produce the greatest amount of nerve stimulation byway of vibration of the facial bones which in turn stimulate the nervessuch as sphenopalatine ganglia, lacrimal nerve, external nasal nerve,infratrochlear nerve, supratraochlear nerve, infraorbital nerve,supraorbital nerve etc. For example, region 2012, when exposed to directskin vibration at approximately 100 Hz-300 Hz vibration produces copiousbilateral tear formation bilaterally when just a single side isstimulated. In some embodiments, vibrations from about 50 Hz to about500 Hz are utilized to stimulate the bones of the face to in turntransmit vibrations to the nerves which stimulate tear production. Thetreatment works best at the resonant frequency of the bone so that thevibration of the bone is maximal and affects the nerve maximally due thegreatest amount of mechanical movement of the nerve and subsequentstimulation. The resonant frequency of the bone is to some extentindividualized per patient. This frequency has been experimentallydetermined and subsequently proven to be in the range of about 100-300Hz.

Region 2014 (FIG. 13) includes the bottom eyelid (inner and outereyelid), the medial canthus of the eye along the nasolacrimal duct.External stimulation along these regions in some embodiments stimulatesthe nerves through bony resonance and in some embodiments, stimulatesthe glands in the lower eyelid region directly.

FIG. 14 depicts neural pathways involved in the transduction ofvibration from the skin to the lacrimal gland when vibrations areapplied through the preferred external location 2012 in FIG. 13. Ganglia2520 projects nerves to the lacrimal nerve 2550 which courses to theorbit to stimulate the main lacrimal gland in the superior portion ofthe orbit. Bone 2530 transmits vibrations to the lacrimal nerve 2550 andaround the maxillary sinus 2500 via the sphenopalatine ganglia. Thesphenopalatine ganglia 2520 is covered by mucosa and sits between theturbinates which are accessible transnasally through the external nasalpassageways 2510. The external nasal nerve is a terminal branch of theophthalmic branch of the trigeminal nerve and is directly stimulatedwith vibration as it is compressed against its exit from underneath thenasal bone at the junction of the nasal bone and the anterior lateralnasal cartilage. In another embodiment, an ultrasound or sound producingprobe is inserted through the external nasal passageways 2510 andapplied to the mucosa in proximity to the sphenopalatine ganglia 2520 tostimulate tear production through direct stimulation or via thenasolacrimal reflex. In another embodiment, a vibratory probe withvibration at approximately 100-300 Hz is inserted into the nasal passageto directly stimulate the sphenopalatine ganglia and/or the interioranterior ethmoidal nerves on the interior of the nasal passage. Inanother embodiment, electrical stimulation of the external nasal nerveaccomplishes tearing by activating the lacrimal nucleus in the pons andsubsequently pre-gangliotic fibers within the maxillary nerve whichsynapse in the sphenopalatine ganglia and then stimulate the lacrimalnerve to produce tears.

In one embodiment, a method to stimulate neural pathways through theapplication of sound or ultrasound energy transcutaneously is described.An applicator is disposed to the face of the patient, the applicatorcomprising one or more vibratory elements capable of generatingvibrations from about 50 Hz to about 50 kHz. The vibration is applied toa region close to a nerve under the skin or to a region with a bonyprominence which communicates via bone structure with a nerve regionlocated close to the skin. For example, an applicator 2000 disposed tothe region 2010, 2012 (FIG. 13) or 2014 (FIGS. 13, 15) will transmit thevibratory energy to the lacrimal glands and produce tears. The resonantfrequency is different for each person as is the exact location anddirection of the vibration. In one embodiment, the individual resonantfrequency is determined and the device adjusted to this frequency foreach person. An interface between the device and the patient's skin issimilarly adjustable so that the vibrations are transmitted to thenerves in the head and neck region to be stimulated. For example, theparasympathetic nerve which innervates the lacrimal gland travels withinthe maxillary bone and the through the sphenopalatine ganglia is locatedclose to the maxillary bone in the sphenopalatine fossa. At a resonantfrequency of the maxillary bone, it has been discovered that the gangliacan be stimulated and tears produced. The resonant frequency is achievedthrough a combination of material, vibration frequency, and amplitude.For example, a material with a durometer between Shore A40 and Shore A60vibrating over a surface area of between 5 mm2 and 20 mm2 with anamplitude of about 0.5 to 5 mm and frequency of between 50 Hz and 400 Hzresults in copious tears. With a directionality upward and at a locationapproximately along the nasal bone where it meets the cartilage, tearscan be produced without discomfort or sneezing or other nasal symptoms.The total force applied over the surface area in some embodiments isabout 1 N (Newton). In other embodiments, the total force is from about0.5 N to bout 2 N. In other embodiments, the force is about 0.25 N toabout 4 N.

FIG. 30 depicts the bony anatomy of the face. FIG. 31 depicts thenervous anatomy of the face. In FIG. 31, at the point where the upperlateral cartilage meets the nasal bone, the external branch of theanterior ethmoidal nerve penetrates the nasal bone is depicted. Thislocation is where the lateral process of the septal nasal cartilagemeets the nasal bone (FIG. 30) and 2012 in FIG. 16. This is thelocation, located on the skin, which has been discovered throughexperimentation to produce tears when mechanical vibration is applied ata frequency of 50-300 with a vibration amplitude of approximately 0.5 mmto 1.5 mm and/or force of about 0.5 to 1.5 N.

Furthermore, it has been discovered that direct stimulation of theinfratrochlear and infraorbital nerves with mechanical vibration alsoinduces lacrimation.

Mechanical vibration can also stimulate lacrimation by direct contactwith the mucosal surfaces inside the nose.

FIG. 31 depicts the neural anatomy of this region underneath the skin.The anterior ethmoidal nerve, a direct continuation of the nasociliarynerve, splits into two branches to supply the nasal mucosa, medial andlateral, as it enters the nasal cavity where is supplies the nasalmucosa. The nasociliary nerve continues to the caudal region of thenasal bone and appears 6.5 mm to 8.5 mm from the midline as the externalnasal nerve (Prendergast in Shaiiman, M A and Giuseppe A D AdvancedAesthetic Rhinoplasty. Springer-Verlag 2013). The infraorbital nerve5010 exits the bone and travels into the skin approximately 1-2 cm belowthe lower eyelid. It is the external nasal nerve which has beendetermined to induce tearing when vibrations at 50-300 Hz are applied.Electrical stimulation (bipolar or monopolar) of the external nasalnerve in this region also can be utilized to induce lacrimation.

A well described pathway for lacrimation is called the nasolacrimalreflex in which stimulation of afferent fibers of the anterior ethmoidalnerve (accessible inside the nose) travel through the ophthalmic nerveto the salivary nucleus in the brain stem (Dart, D A Prog Retin EyeDisease 2009; May 28(3): 155-177), then parasympathetic nerve signalstravel via the maxillary branch of the trigeminal synapse in thesphenopalatine ganglia to innervate the lacrimal nerve and stimulate thelacrimal glands. Parasympathetic fibers generally stimulate the lacrimalglands and also partially innervate the Meibomian glands.

In addition to the specific descriptions set forth herein, it has beendiscovered through extensive experimentation that stimulation of theexternal nasal nerve achieves lacrimation. As described above, theexternal nasal nerve 5020 exits deep to the layers of the skin throughan orifice 5270 at the junction of the nasal cartilage 5240 and nasalbone 5210. It is not accessible by electrical stimulation. As describedherein, certain vibrational parameters result in stimulation oflacrimation similar to the nasolacrimal reflex.

Han et. al (Plast Reconstr Surg 114: 1055, 2004) characterized theanatomy of the external nasal nerve in cadaver specimens. The externalnasal nerve is a continuation of the nasociliary nerve which originatesfrom the ophthalmic branch of the trigeminal nerve. Prior to its exitfrom the inner portion of the nose to the external portion of the nose,it gives off two branches to the inner portion of the nose. The externalnasal branch is the terminal nerve of the nasociliary nerve. Afterexiting the inner portion of the nose between the nasal bone and theupper lateral cartilage (through a notch in the nasal bone), theexternal nasal nerve dips into the fibrofatty tissue to ultimatelybranch and supply the skin and fatty tissues of the distal nose. Theexit was consistently 6.5-8.5 mm lateral to the nasal midlineindependent of the width of nose. There were there branching patternsidentified. The first was a single nerve exiting the nasal bone. Thesecond pattern was splitting of the nerve upon exit from the nasal boneand the third pattern was splitting of the nerve distal to the exit fromthe nasal bone close to the cartilage of the distal region of the nose.The nerve size in this study was consistently 0.3 mm to 0.4 mm diameter.

Therefore, in one embodiment, a device is placed approximately 6.5 to8.5 mm lateral to the nasal midline at the region where the upperlateral cartilage meets the nasal bone. The device is placedunilaterally or bilaterally or unilaterally and then sequentially on thecontralateral side for bilateral treatment. The device applies a forceover an are of 1-2 mm² on the nose at frequency of 100-300 Hz. In someembodiments, approximately 0.5 to about 2.0 Newtons (N) of force isapplied to the external nasasl nerve as it leaves the nasal bone. Inother embodiments, a force of approximately 2 to about 5 N is applied tothe nose to activate the external nasal nerve.

In another embodiment in FIG. 15, the nasolacrimal duct is the target.It has been found in clinical work that stimulation of this ductinternally along its length leads to stimulation of tear production. Themechanism is thought to be direct stimulation of the nasolacrimalreflex. In this invention, it has been further discovered that vibrationat 100-500 Hz externally through the skin in the region of the bonethrough which the duct travels (e.g. nasal bone) also stimulates thisreflex. Similar to the external nasal nerve, electrical stimulation hasbeen found to be ineffective in the stimulation of the reflex throughthis anatomy

The effector interface with the face of the patient is a very importantcomponent of the energy transmission to promote safety and tolerabilityof the procedure. Through experimentation, the optimal durometer issomewhere between Shore 40A (pencil eraser) and Shore 80A (leather).Shore 60A is about a car tire tread and Shore 70A is a running shoesole. With an interface which is too hard, the skin is abraded and withan interface which is too soft, the nerve is not effectively stimulated.

It has been determined that unfocused vibration at 50 Hz to about 300 Hzleads to general activation of the sphenopalatine ganglion, lacrimalnerve, external nasal nerve, infratrochlear nerve, infraorbital nerve,supraorbital nerve, or internal nasal nerve leading to inhibition ofrhinitis like symptoms by overstimulation and/or relief from nasalcongestion, migraines, narcolepsy, dry mouth, dry eye, and elevatedintra-ocular pressure via neuromodulation. Focused, or directedvibration, be it sound in which the vibrating waves are directed towardthe skin and bone by way of positioning the probe toward thenasopalatine ganglia, external nasal nerves, or eyelids, or lacrimalnerves have been determined to be more effective in eliciting specificpathways such as lacrimation.

FIG. 16 depicts a device usable to activate the lacrimation pathway byapplying vibration to the side of the nose and/or lacrimal pathway toactivate the external nasal nerve as it exits the nasal bone onto theskin of the nose. Vibratory energy at 100-300 Hz with 1 mm excursion and1-4 N of force stimulates the external nasal nerve when then energy isapplied to the region with a sufficiently rigid biocompatible material.

In another preferred embodiment, the vibration is applied directly tothe conjunctival region of the eyelid to stimulate tears directly bystimulating the accessory lacrimal glands in the lower lid and the smallmuscles that surround each of the Meibomian glands.

In one embodiment, the end effector of device 2000 is applied directlyto the lacrimal gland 2100 or to the mucosa of the inner eyelid. Device2000 is configured in one embodiment to run along the inner eyelid whilethe eyelid is being retracted to create tears, stimulate Meibomianglands, etc. In one embodiment, device 2000 is depressed against theskin of the nose in the region where the nasal cartilage meets the nasalbone (aka the nasal ala) 2012 where the cartilage and nasal bone meetalong the side of the nose of the patient at the region where theexternal nasal nerve exits the nasal bone.

Therefore, in one embodiment, a vibratory device is applied to theskin/mucosa of the inner eyelid, applying an end effector moving atabout 50-300 Hz with the end effector moving approximately 250 micronsto 2 mm in excursion with 0.5 to 2 N of force, the end effector having abiocompatible material with durometer between about 60 A and 100 A and atip which applies the force to the skin over an area of about 1 mm² to 5mm². Pulsed frequencies (on-off) can enhance the effect. For example,the vibration can be applied with a 50% duty cycle or a 25% duty cyclewith a peak amplitude greater than the base amplitude.

FIG. 17 depicts the structural details of the ultrasound transmissionfrom the skin through the bone and to the nerves which lie beneath thebones of the face. The end effector 2004 of the device 2002 communicateswith the skin 2050 and from there, the vibrations travel through theskin 2050 to the bone 2052 and to the mucous layer 2054 underneath. Fromthe bone, the vibration can be transmitted to the nerves in otherregions of the face such as the sphenopalatine ganglia, the infraorbitalnerve, the orbital nerve, the facial nerve, the trigeminal nerve, theethmoidal nerve, and ultimately, the lacrimal nerve.

Direct stimulation of the mucous layer through bone also will accomplishdirect treatment of sinus disease in addition to its effect on thenerves. Vibration and/or ultrasound stimulation of the mucosal layerswill affect congestion directly by unplugging the outflow pathways andequalizing pressure.

FIG. 18 depicts several of the bony pathways which can communicate withnerve pathways via neuroacoustic conduction present inside the cranium2150 and facial bones. The maxillary sinus and bone 2170 are thepredominant pathway for transmission of vibratory energy to thesphenopalatine ganglia and ultimately the lacrimal nerve and gland. Theconchae 2195 are folds of the maxillary bone which protrude partiallyinto the nasal cavity. The conchae protect the olfactory bulb as well asthe sphenopalatine ganglia but also play a role in transmission ofsounds. The maxillary bone and its conchae communicate with thezygomatic bone 2190. The mandible 2180 represents an additional, albeitless direct pathway, for stimulation of the nerves of the facial region.In a preferred embodiment, a resonant frequency for these bones isutilized in order to transmit vibrational energy to the nerves within orbelow the bone to achieve a clinical end such as generating tears in theeye, stopping cluster headaches, migraines, seizures, rhinitis, andnasal congestion.

FIGS. 19-21 depict various end effectors 2004 (FIG. 17) of the device2000 through which the vibratory energy is delivered transcutaneously tostimulate nerves of the facial regions, specifically the external nasalnerve.

FIG. 19 depicts an effector which is approximately 5 mm in diameter andlonger than 2 cm. The tip is relatively flat and soft so that it can bedepressed against the skin along the side of the nose to couple energyto the bone and the nerves beneath. The tip 2200 is rounded at its endand may be produced from a hydrophilic substance or a hydrogel or a morefirm, harder material to facilitate coupling with the skin. A portion ofthe tip is more firm and rigid than another portion so that vibrationalenergy has a preferential direction as it is transmitted to and throughthe skin.

FIG. 19a depicts optional rings 2202 or constraining structures whichcircumscribe the tissue-engaging end of the tip to further enhance theability of the tip to transfer vibrational energy into the skin.

FIG. 20 depicts another embodiment of an end effector to transmit energythrough the skin to the bones and to the nerves underneath. In thisexample, the end effector is in the form of a small paddle 2210 with athin flexible neck 2212 which can be applied to the skin regions whichtransmit vibratory energy to nerves. This embodiment allows the user toapply a variable pressure to the skin to modulate the vibration throughthe skin and bone to the nerve.

FIG. 21 is another embodiment of an end effector. In this example, theend effector 2222 is soft and compliant with an outer layer 2220 madefrom a hydrogel or other slippery material. A backing layer is disposedoutside the slippery material so that the end effector can be depressedagainst the skin. The end effector may have an edge between 1 and 5 mmthick, the end (edge radius) being rigid so it may be depressed in theridge on the side of the nose where the nasal cartilage meets the bone.The end can be rounded in some embodiments with a radius of curvature of0.5 mm to 5 mm. The lateral curvature of the edge determines thesharpness of the tip, a key factor in the stimulation of the externalnasal nerve. The smaller the radius and more severe the drop off alongthe radius to the outermost edge of the tip, the sharper the tipbecomes.

In another embodiment, a method is described in which a location ofmaximal tear activity is determined by moving the applicator tip todifferent positions and angles.

FIGS. 22-23. In another embodiment, a device is depicted which isdesigned to deliver focused ultrasound energy to the retina of an eye.FIGS. 22 and 23 depict a device and simulation respectively of thedevice on the tissues of the eye. Device 2410 is a ring shaped focusedultrasound transducer which is applied to the scleral region around thepupil 2420. FIG. 23 depicts the ultrasound field 2455 created by thetransducer design. Ultrasound is focused at the back of the eye on theretina in this embodiment. The field is produced such that lens isspared and the surface intensity of the design is minimized so as toprevent damage to the sclera, trabecular meshwork, ciliary bodies, etc.

FIG. 24 depicts an experiment 2500 on human subjects performed with anembodiment of the current invention. With a constant amplitude ofapproximately 1 mm, a variable frequency was applied to the teargeneration regions in and around the eye discussed herein. Teargeneration was measured with a Schirmer test in which volume of tears isquantified with a test strip. It was found that at the extremes of thefrequency (e.g. 50 Hz and 1000 Hz), there is very little response as faras tear generation and that tear generation peaked (using a Schirmertest to quantify the volume to tears) at about between 200 and 300 Hz.Furthermore, outside of the tear generation points on the face, therewas no generation of tears in the patients. For example, application ofthe device to the lips, the distal edge of the nose, the forehead abovethe eyebrows, and the teeth did not result in tear generation showingthat indeed it is frequency and position which are most important tostimulating the lacrimal glands. The external nasal nerve was directlystimulated when the device was compressed against the nasal bone wherethe upper lateral nasal cartilage meets the nasal bone and a frequencyof about 200-300 Hz is applied using amplitude of about 1-2 mm.

FIG. 25 depicts a close up configuration of a device 2800 to treatMeibomiam gland disease in dry eye. An eyelid region between 2830 and2840 is depicted between an end of a lid retractor edge 2840 and aflexible component of the retractor 2830 which is configured to enablepressure to the eyelid which is sandwiched between the flexiblecomponent 2830 and the tip of the retractor 2840. Element 2810 is alever for the user to control the pressure and manipulate flexiblecomponent 2820 and 2830. In another embodiment, component 2820 and 2830are not flexible but is a vibrating element such as a linear resonantactuator (LRA) which can vibrate at the optimal frequencies determinedby the experiment shown in FIG. 24. In some embodiments, element 2820and 2830 are flexible and vibrate.

This device 2800 combines pressure along with the ability of the user to“milk” the glands while the eyelid is being retracted away from thesclera. Vibration and heat are also optionally provided by the device soas to create synergistic effects on the glands and lids.

FIG. 26 depicts an embodiment of a device to apply several forms ofenergy to an eyelid. The eyelid is positioned between a retractor member3020 and a pushrod member 3010. Inner shaft 3060 slides along outershaft 3080 to move the pusher member 3010 so it applies pressure to theeyelid between the inside of the retractor member 3020 and the pushablemember 3040. Inner member 3060 is attached to housing 3042 by a springwhich retracts the inner member when the operator of the device releasesthe inner member 3060. Without operator application of force to theinner member, the inner member springs back to the baseline state whereno pressure is applied to the eyelid. Such design is created for safety.Without operator force, the inner member is harmless because it retractsinto the housing 3042. The spring on the inner member can also be usedto measure or quantify the force being applied to the eyelid so that theoperator of the device will have a sense of how much pressure he or sheis applying. The force which is applied can be signaled to the user ofthe device with vibration or sound to indicate when a safe and properforce is being applied to the eyelid.

The device in FIG. 26 optionally contains an ultrasound element 3030 onthe inner shaft 3010 and/or the outer shaft 3020 which can generateultrasound at frequencies from between 20 KHz to 30 MHz. In a preferredembodiment, the frequency is between 3 MHz and 10 MHz or between 500 kHzand 3 MHz depending on the desired effect. Ultrasound at thesefrequencies efficiently generates heat into the eyelid and can alsobreak up the inspissation in the blocked ducts. Importantly, heat isdelivered to the inside of the eyelid via ultrasound which penetratesthe eyelid and effectively heats at tissue planes inside the lid. Heatis not delivered via conduction from the outer or inner lid to theglands as it is in all devices in widespread use today. Rather, heat isapplied to and through the eyelid via a non-conductive process. Thesurface and skin of the eyelid remain at body temperature (38-40 C) orslightly above while the inner eyelid is heated to over 42 C (42-48 C).Furthermore, vibratory devices 3050, 3065 are incorporated into theouter shaft 308 or inner shaft 3060 respectively which can addadditional mechanical energy to the eyelid. The vibration frequency canrange anywhere from about 50 Hz to about 500 Hz with an amplitude ofanywhere from about 100 microns to 3 mm as depicted in FIG. 24 anddescribed above. Either the inner member 3010 and/or the outer member3020 optionally contain a temperature sensing element such as athermistor as well as closed loop control of the heating based on thetemperature. In one embodiment, a control circuit is integrated intodevice 3000.

In another embodiment, element 3030 is a light emitting diode or similarheat generating element. An infrared diode will generate infrared energythrough the eyelid and also heat the glands non-invasively.

Device 3000 preferably contains self-contained power supply which isrechargeable. A base can be provided which contains a power supply is torecharge the device 3000. In some embodiments, the rechargeable powersupply is built into device 3000 and the entire unit is rechargeable.

FIG. 27 depicts a larger view of the retractor device 3500 with theinner pushrod 3540 and outer retractor 3520 along with the vibratoryelement 3550. Ultrasound elements 3530 and 3535 are configured todeliver ultrasonic energy to the eyelid which is compressed between theinner pushrod 3540 and the outer lid retractor element 3520. Element3515 is a connector to enable the inner pushrod to spring backautomatically to the home position (shown in FIG. 27). Because element3515 in some embodiments is elastic, it enables quantification of theforce applied to the eyelid and/or springs back during application forquick release if there is patient discomfort.

Vibrating element 3550 transmits vibration to the tip through the curvedportion of the retractor 3520. The tip 3525 contacts the conjunctiva atthe mucocutaneous junction of the inner eyelid to create tears,stimulate the Meibomian glands to open and to induce secretion of lipidsand oils from the glands to produce a long lasting tear film.Additionally, the embodiment in FIG. 27 comprises range finding elementssuch as a camera, laser, or ultrasound range finder which can beutilized to mark the distance of the device from the surface of the eyeso that it is considered a safe device and procedure. In thisembodiment, when the vibrating tip is placed too close to the eyewithout retraction of the eyelid away from the sclera of the eye, ashutdown occurs and the device does not operate.

Device 3500 enables a method whereby the eyelid is retracted withretractor 3525, push rod 3540 is pressed against the outer eyelid andthe eyelid is compressed between retractor 3520 and pushrod 3540, thepressure optionally measured by elastic recoil element 3515. Heat andvibration from ultrasound element 3535 is applied to the eyelid tocreate tearing, break up inspissations in the Meibomian glands, andstimulate the glands to secrete oils and proteinaceous materials.Pressure can be quantified and controlled using elastic element 3515.The eyeball, sclera, cornea, etc. are protected from heat, ultrasound,and pressure via the retractor which pulls away the lower eyelid.Thermistor 3535 allows for temperature measurement and control of theultrasound power so that the element does not overheat and the tissue isnot burned. The operator can set the temperature limit within aspecified range, for example, 42 C to 48 C.

Further treatment effect can be achieved in one embodiment withmechanical vibration using linear resonant actuators or similarvibrating elements on the implement 3550 and 3510. These mechanicalvibrators which vibrate at between 200 and 300 Hz can be used alone orin combination with the rest of the device to open Meibomian glands andstimulate nerves to secrete tears, oils, and proteinaceous materials.

FIG. 28 is an expanded view of the device with the ultrasound element4025 on the inside 4035. “Inside” refers to the pushrod 4035 whichcontacts the outer portion of the eyelid. In this embodiment, theultrasound element contacts the outer portion of the eyelid but in otherembodiments, the ultrasound element contacts the inside of the eyelid inwhich case it is placed on the retractor portion 4045 of the device4000. In some embodiments, the ultrasound elements 4025 are placed suchthat they contact both the inside and outside of the eyelid. Linearresonant actuators (LRA) 4040 can be similarly placed on both the outerand inner components or just one or the other components. In someembodiments, a voice coil is used and actuated via portable battery.Wire 4030 may carry current or is flexible or both. It is connected tothe inner pushrod 4035 to stabilize it, retract it, or carry electricalcurrent to the tip of device 4000. If flexible, it can be attached to astrain gauge or pressure sensor. In one embodiment, the flexible wire isconfigured such that it retracts the inner pushrod back from theposition in which the eyelid is pressurized by the inner and outerpushrods. Through hole 4050 houses the elastic band or wire 4030 throughwhich it anchors in housing 4055. Housing 4055 may contain a DC batteryand circuitry to drive the LRA. Outer retractor 4045 is composed of acomfortable and biocompatible material to retract the eyelid. Forexample, outer retractor 4045 is made from a hydrogel or a PTFEmaterial. In another embodiment, outer retractor 4045 is made from aspongy material with some compliance when depressed against a lid. Anadvantage of placing the ultrasound transducers on pushrod 4035 tocontact the outer portion of the lid is that the outer retractor 4045may be optimized for comfort without the additional compromise of havingpiezoelectric materials for ultrasound generation embedded inside.

FIG. 29 depicts the expanded components of one embodiment of a device tostimulate tears 4100. 4120 is the housing with an advanced userinterface to allow for gripping the device and then applying to theexternal nasal nerve of a patient. Grip 4125 is a user interface for thedevice which contacts the palm of the user to allow for manipulation ofthe device while the biocompatible tip 4150 is manipulated and appliedto the skin of the patient. The material is biocompatible and firm.Speaker or voice coil 4135 is the heart of the system, allowing for acontinuous spectrum of frequencies, from 50 Hz all the way to kHzfrequency as well as modulation of driving amplitude. Skin interface4150 is stabilized by frame 4110. Frame 4110 also enables finger gripsfor further manipulation of the device. The skin interface 4150 is abiocompatible skin interface which allows for the application of cyclicforce to the external nasal nerve, compressing the nerve against thenasal bone at a frequency of approximately 175 Hz to stimulate the nerveto generate tears. Shaft 4130 underneath the end effector is driven bythe speaker to then drive the end effector element 4150. Interface 4140provides the transduction interface between the speaker 4135 and the endeffector 4150.

FIG. 30 depicts nasal anatomy. The frontal bone 5150 forms the upperboundary of the orbit and maxillary bone 5205 forms the medial boundaryof the orbit. The frontal bone forms the roof of the frontal sinus.Maxillary bone forms the roof of the maxillary sinus 5260. The nares5310 is the communication between the outside and the internal mucosa ofthe nose. The external nasal nerve 5215 leaves the nasal cavity throughan orifice 5215 between the nasal bone 5200 and the lateral processes ofthe septal nasal cartilage 5210. It has been discovered that stimulationof the external nasal nerve in this region 5215 with force between 1-4 Nusing vibration at 100-300 Hz results in several clinical effectsincluding creation of tears, abrogation of allergic and vasomotorrhinitis, relief from sinusitis, stimulation of Meibomian glands,treatment of headaches, and narcolepsy.

FIG. 31 depicts the cutaneous nervous anatomy 5000 in and around thenasal cavity. Cutaneous, or subcutaneous, generally refers to nervescovered by skin, dead stratified squamous, keratinized epithelial cells.In contrast, mucosa or sub-mucosal, nerves are covered bynon-keratinized mucosal epithelial cells which are generally ciliatedand columnar. Cutaneous nerves are more difficult to reach with certainenergy forms (e.g. electrical stimulation) because the dead stratifiedlayers broadly diffuse the current. However, vibratory stimulation canbe directed to the nerves underlying the skin by transmission ofpressure waves. The external branch of the anterior ethmoidal nerve5020, also referred to as the external nasal nerve, exits at the caudalportion of the nasal bone and supplies the ipsilateral side of the nosewith cutaneous nerve fibers. Infraorbital nerve 5010 supplies cutaneousfibers to the lower eyelid, upper lip, and a portion of the nasalvestibule; the vestibule is the most anterior part of the nose, lined bythe same epithelium as the skin. Its epithelium transitions to therespiratory epithelium of the nasal cavity proper. The infratrochlearnerve 5035 supplies the skin of the upper eyelids, bridge of the nose,the conjunctiva, lacrimal sac, and the caruncle (small, pink, globularnodule at the inner corner of the eye made of skin covering thesebaceous and sweat glands). The supratrochlear nerve 5030 supplies theskin of the lower forehead, the conjunctiva and the skin of the uppereyelid. It has been discovered through experimentation described hereinthat vibratory stimuli (e.g. 50 Hz to approximately 300 Hz) of thesenerves and nerve endings stimulate the lacrimal nerve to secrete tears.In these embodiments, the vibratory stimuli contact the stratifiedepithelium of the skin not the mucosa and energy is transferred bymechanical waves.

In one embodiment, the lacrimal gland is activated by stimulating theinfraorbital nerve, the infratrochlear nerve, the supratrochlear nerve,the caruncle or the conjunctiva inside the eyelids. Indeed, theconjunctiva inside the eyelids or on the surface of the eye is mucosaand the upper layers are non-keratinized. Stimulation of these tissuesis optionally performed with vibratory energy including sound,ultrasound, mechanical vibration, electrical sparking, puff of air, puffor water or other liquid, or other mechanically sharp stimulationimpulse. In the mucosal tissues, electrical stimulation is also morepossible because of the lack of stratified epidermis diffusing thecurrent. Therefore, in one embodiment, current is passed through theconjunctiva of the eye to stimulate tears.

FIG. 32 depicts an embodiment of the current invention 5300. Stimulationdevice 5310 couples to the finger of a subject. In this embodiment, thepatient or the user retracts their eyelid with his or her finger andapplies the stimulation to the eyelid with another finger. In oneexample, this embodiment incorporates a linear resonant actuator with anedge configured for application to the eyelid. In another embodiment,electrodes on the device deliver current across the mucosa. Thefingertip is chosen in this embodiment as it affords the user to finelymanipulate the vibration or other energy which is very important whenapplying energy around the eyelid.

FIG. 33 depicts the components of the finger stimulation device 5400shown in FIG. 32. Linear resonant actuator (LRA) 5450 couples to endeffector 5460 which contacts the caudal portion of the nasal bone at theexit of the external nasal nerve. The linear resonance actuator isconfigured to generate linear motion and apply a force of between 1 and5 Newtons or 2-5 lbs. Backing 5440 directs the LRA 5450 andbiocompatible interface 5460 to a predominantly linear direction tomaximize the energy applied against the nerve. The power button anddriving circuit 5410 is powered by a rechargeable battery 5420.

FIG. 34 depicts a handheld embodiment of a device 5500 to applyvibrational energy to the facial region in which there is an underlyingparasympathetic nerve or a circuit which ultimately results instimulation of a parasympathetic nerve. Interface 5510 moves with linearexcursion substantially perpendicular to the housing 5520. Housing 5520is configured to be handheld and self-contained, produced from acomfortable, biocompatible plastic or aluminum material. Interface 5510is fairly rigid with a rounded yet firm tip. The radius of curvature ofthe tip is such that it can firmly push into the junction of the nasalcartilage and nasal bone, vibrate a 100-300 Hz, preferably between 180and 220 Hz or at least between 75 Hz and 300 Hz with maintenance of aconstant speed despite the force being applied by the user to the nerve.

FIG. 35 depicts a detailed view of the handheld device in FIG. 34. Thebasic mechanism of this device is a voice coil 5590 which provides for alinear driving motion of the tip 5570. Plastic body 5560, 5592 surroundsthe device. An optical distance sensor 5580 is calibrated to detectmovement of the linear vibrating component 5570. Printed circuit boardassembly 5594 comprises an amplifier and battery charging circuitry aswell as an optional control system so that the tip 5570 vibrates at anear constant frequency. Power button 5596 and cover 5592 as well aslithium ion batteries 5584 and 5586 complete the unit. This unit isself-contained and the lithium ion batteries are rechargeable.

FIG. 36 depicts the components of a vibratory device 5600 which isconfigured to be held in the palm of the hand of the user with aninterface with the tip of a finger of a user. Body surface interface5650 is configured to be handheld and comfort grip 5694 is configuredfrom a biocompatible material. Lithium ion 5692 battery is inserted intothe main body housing 5640. Linear vibration motor 5650 travels withlinear motion and is connected to the body surface interface to createlinear motion as well. The surface interface is applied to the skin withperpendicular application to the skin to stimulate the external nasalnerve and the parasympathetic nervous system to open Meibomian glands,create secretions of oils, and produce tears from the lacrimal glands,treat migraines, epilepsy, narcolepsy, headaches, open blood brainbarrier, equalize pressure, treat rhinitis and sinusitis, and nasalpolyps. Tactile switches 5660 enable user guided feedback to increase ordecrease stimulation level, either by signaling adjustment of thevibration amplitude and/or frequency.

FIG. 37 depicts another embodiment of a device 6000 configured to applyvibrational energy to a nerve overlying a parasympathetic nerve of theface. Interface 6020 is a biocompatible skin interface designed totransfer force from the vibratory element to the skin overlying the boneof the patient and to the nerve underlying the bone. A snap element 6010allows for quick placement and removal of the skin interface 6020. Thevibration is generated by eccentric motor 6040 which vibrates thebiocompatible interface with an approximately planar and perpendicularvibratory direction to the long axis of the device 6000. Switch 6055powers the device on and off. Rechargeable battery 6060 and electricalaccess port 6070 enable power delivery to the device 6000. Additionalelectronics 6045 may include a lockout timer so that a user does notover use the device. A control system to maintain a pre-specified motorand vibration speed is also an optional feature of the circuitry. Theelectronics are housed in shell 6050.

FIG. 38 depicts an embodiment of a vibratory device 6000 in whichvibratory energy is applied to the mucocutaneous junction where the skinof the eyelid meets the conjunctiva. The nerve endings of the eyelid arestimulated in this embodiment and energy is applied to the mucocutaneousjunction to create tears and unblock and stimulate Meibomian glands.Device 6000 comprises a vibratory, sound, or ultrasound generatingcomponent which can be coupled to the eyelid. In one embodiment, thedevice further incorporates suction to grab on to the eyelid during thetreatment. In another embodiment, the device incorporates a grip like apair of tweezers or forceps to hold the eyelid while the energy isapplied.

FIG. 39 depicts the inner workings 6100 of the device in FIG. 38 whichapplies vibrational energy to the mucocutaneous junction of the eyelid.Pressure sensitive switch 6110 controls the vibrational energy withpressure. Importantly, eyelid interface 6140 in configured to interfacewith the eyelid. It is comprised of a biocompatible material andcomprises a mechanism to pull away the eyelid while applying vibrationor ultrasound so as to protect the sclera and cornea. A standard motor6120 drives the device 6100. Optionally, the motor 6120 is connected toa weight 6130 to create eccentricity and vibration. Elastomer pad 6150is a biocompatible interface with the skin of the patient or deviceuser. The pad is characterized by a shore durometer of between 20A and50A. In another embodiment, a linear resonant actuator is utilized tocouple vibration to the mucocutaneous junction of the eyelid. In thisembodiment, vibrations of about 50 to 300 Hz have been found to beoptimal to stimulate the nerve endings in the conjunctiva present on theeyelid. The pathway in this embodiment is presumed to be both a neuralreflex pathway and mechanical pathway in which the glands arestimulated.

FIG. 40 depicts a component break out of the device in FIGS. 38 and 39.6210 is a pressure sensitive switch which when depressed creates alarger vibration excursion or less excursion depending on what the userprefers. 6220 is a top cover for the device and 6250 is an eccentricallyweighted motor. The motor is connected to the drive shaft 6270 to movethe biocompatible patient interface 6275. The device is housed withaluminum 6260 or plastic with smooth edges. Rechargeable battery 6240 isregulated by voltage regulator 6230 to supply DC motor 6250. DC motor6250 almost might be linked to a rotating cam to move a piston in adirection perpendicular to the motor to then be applied to the skin of apatient to activate a nerve through the skin.

FIGS. 41-42 depict an embodiment wherein the vibrating elements areattached to the fingertips of the patient. Linear resonant actuators oreccentric motors are utilized in the fingertip devices. Fingerband 6405allows the user's finger to be attached to the device. Biocompatiblecoupling 6420, 6430 facilitates the user application of the device tothe skin of the user. Pressure sensor 6407 allows pressure controlledmodulation of the frequency or amplitude of the end effectors whichprovide the energy to the skin of the user.

FIG. 43 depicts a device 7000 which can be applied bilaterally to thenose of a patient to stimulate the external nasal nerve simultaneouslyor individually depending on patient preference. A feature of thisdevice is that it has haptic feedback such that as the patient pressesdown on the device and on the nose, the device responds by applying agreater force or displacement to ensure nerve stimulation.

FIG. 44 depicts the underside of the device shown in FIG. 43. Pressuresensors 7850 sense the force being applied by the user. Material 7855 ispreferably flexible so that the user can squeeze the device and compressthe external nasal nerve and apply increasing vibrational force, thedegree of which is dictated by the force the pressure sensor senses onthe skin. The device Is rechargeable via port 7860 which can alsopotentially serve as a data port.

FIG. 45 depicts a schematic of a portion of the device shown in FIG. 42.The drive electronics and programming are contained in this component ofthe device from FIG. 42 and is designed to fit in the palm of the handof the user. Cables 6432 extend to the finger effectors and fingerstraps shown in FIG. 42. Lithium ion battery allows for recharging ofthe unit. Switch 6440 is a voice activated switch or simple toggleon-off which is activated by the user. Plastic body 6450 houses thecircuitry and battery and is comprised of aluminum of plastic. Circuitboard assembly 6470 contains control circuitry including voltageregulator and optionally feedback so that the motors can operatecontinuously.

FIG. 46 depicts a schematic of the individual components of the deviceshown in FIG. 43. Pressure sensors 8010 enable coupling between theforce applied by the user and the speed, torque, and force of theeccentric motors 8020 which create the vibratory effect to stimulate theexternal nasal nerve and parasympathetic pathway. Element 8030 is ahousing for electronics and for the patient to grip while applying thevibration to the external nasal nerve and parasympathetic pathway.Battery 8040 is preferably rechargeable but also may be a replaceablebattery. Cover 8070 seals the electronic circuit board 8050 and chargeport 8060.

FIG. 47 depicts a preferred embodiment 8100 in which the end effectorinterface 8110 moves in a linear direction, actuated by a cam 8150mechanically connected 8140 to an electric motor 8160. Rotation of themotor linked to the cam 8150 drives a piston 8120 with an end 8110 whichalso serves as the biocompatible interface with an edge adapted toactivate a nerve such as the external nasal nerve. The piston 8120 andbiocompatible interface 8110 move at an optimal frequency between 100and 300 Hz or between 50 Hz and 400 Hz. The cam 8150 can be offset fromthe central axis 8140 to determine the excursion of the piston (e.g. 1mm) and interface which then applies force to the skin of the patientand then to the nerve to be stimulated. In some embodiments, a governoris included to ensure that the frequency that is set by the user orpre-determined before delivery to the user is the actual frequency ofthe piston excursion. For example, in one embodiment, a photodiode orother detector is utilized to detect motion of the electric motor,linkages, or the piston; if the revolutions per minute (RPM) are not aspre-specified, additional current is added or subtracted from the motor.Electronic circuitry is also included which enables the device to recordthe time of treatment, time between treatments as well as a lock outtime in between treatments (e.g. to ensure that the device is notoverused or underused). Such data is stored in memory and isdownloadable offline to a PC as a record of usage and compliance withthe device in real world practice or in a clinical trial setting. Thecircuit further controls the voltage to ensure a constant power to themotor and constant rotation which can be pre-set or varied by the user.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following clauses define the scope of the invention and that methodsand structures within the scope of these clauses and their equivalentsbe covered thereby.

What is claimed is:
 1. A method for treating a patient having dry eye tostimulate tear or meibomian gland secretion, said method comprising:providing an applicator comprising a housing having a vibratory surfacewith a skin contact area in a range from 0.5 mm² to 10 mm² and aself-contained actuation mechanism configured to vibrate the vibratorysurface; wherein the patient holds the housing in a hand and presses thevibratory surface against a target location on the patient's face;wherein the target location is a region on the patient's face at ajunction of the patient's nasal cartilage and nasal bone over thepatient's external nasal nerve; and wherein the patient presses thevibratory surface against the target location with a force in a rangefrom 0.5 N to 5 N while the vibratory surface vibrates at a frequency ina range from 100 Hz to 500 Hz with a displacement in a range from 0.1 mmto 3 mm to mechanically stimulate the patient's external nasal nerve toproduce tears.
 2. The method of claim 1, wherein the vibratory surfaceis configured to fit in a ridge at the junction of the nasal bone andnasal cartilage.
 3. The method of claim 2, the vibratory surfacecomprises a rounded edge having a radius in a range from 0.5 mm to 5 mmand a thickness in a range from 1 mm to 5 mm.
 4. The method of claim 1,wherein the vibratory surface is displaced in a linear motionsubstantially perpendicular to a surface of the housing.
 5. The methodof claim 1, wherein the vibratory surface is pressed into the junctionof the nasal bone and the anterior lateral nasal cartilage
 6. The methodof claim 5, wherein the vibratory surface has an edge with a thicknessradius sized to be pressed into the junction of the nasal bone and theanterior lateral nasal cartilage.
 7. The method of claim 6, wherein thethickness radius is in a range between 0.5 mm and 5 mm.
 8. The method ofclaim 1, wherein the housing is pressed against the target location withan upward directionality to firmly engage the target location along alateral interface between the nasal bone and the nasal cartilage.
 9. Themethod of claim 8, wherein the vibratory surface comprises an edge witha curved surface and compliant member attached to the housing, whereinthe edge is pressed against the target location to transmit vibratoryenergy to the patient's external nasal nerve.
 10. The method of claim 9,wherein the patient presses the vibratory surface against the targetlocation with a variable pressure to modulate a vibration deliveredthrough the skin and bone to the patient's external nasal nerve.
 11. Themethod of claim 1, wherein the vibratory surface has a hardness in arange from Shore A40 to Shore A80.